ClinVar Genomic variation as it relates to human health

In patients from 3 unrelated families with familial aminoglycoside-induced deafness (580000) and in a large Arab Israeli pedigree with nonsyndromic deafness (500008), Prezant et al. (1993) found a 1555A-G transition in the 12S rRNA gene (MTRNR1), a site implicated in aminoglycoside activity by analogy to the evolutionarily related bacterial ribosome. Hutchin et al. (1993) found the same mutation in 2 Japanese pedigrees and 3 Chinese pedigrees with aminoglycoside-induced deafness and in 4 of 74 sporadic deafness cases thought to be the result of exposure to aminoglycosides. The frequency of the mutation in the hearing population was less than 1 in 200. The 1555A-G mutation was inferred to create a new basepair at the terminus of the penultimate helix of the 12S RNA. Hutchin et al. (1993) proposed that this additional basepair decreases the molecular volume taken up by RNA at this site relative to the unpaired bases, thus increasing the size of the aminoglycoside binding pocket and making aminoglycoside binding tighter. Pandya et al. (1997) ascertained 3 Mongolian pedigrees from a school for the deaf and blind, which contained multiple affected subjects with streptomycin-induced deafness in a pattern consistent with matrilineal transmission. In 2 of the 3 families they found the 1555A-G mutation in the 12S rRNA gene by restriction analysis as well as by direct sequencing. No other example of this substitution was found among 400 control samples from Mongolians with normal hearing. In countries where aminoglycosides are widely used, genetic counseling and screening of high-risk families before the use of these drugs could have a dramatic effect on the incidence of deafness. Gardner et al. (1997) reported the 1555A-G point mutation in the 12S ribosomal RNA gene in a South African family with streptomycin-induced sensorineural deafness. They came to the same conclusions as Pandya et al. (1997) regarding the usefulness of genetic counseling and screening of high-risk families in countries where aminoglycosides are widely used. Estivill et al. (1998) studied 70 Spanish families with sensorineural deafness (36 congenital and 34 late-onset) for the mtDNA 1555A-G mutation. The mutation was found in 19 families with maternally transmitted deafness but not in the other 51 families or in 200 control subjects. In 12 families, all the patients with the 1555A-G mutation who received aminoglycosides became deaf, representing 30.3% of the deaf patients in these families. None of the deaf patients from 7 other families received aminoglycosides. Overall, only 17.7% of the patients with deafness and the 1555A-G mutation had been treated with aminoglycosides. The age at onset of deafness was lower (median age 5 years, range 1 to 52 years) in those treated with aminoglycosides than in those who did not receive aminoglycosides (median age 20 years, range 1 to 65 years). The mtDNA of these families belonged to haplotypes common in Europeans. Data indicated that the 1555A-G mutation accounts for a large proportion of the Spanish families with late-onset sensorineural deafness, that the 1555A-G mutation has an age-dependent penetrance for deafness (enhanced by treatment with aminoglycosides), and that mtDNA backgrounds probably do not play a major role in disease expression. Abe et al. (1998) performed a phylogenetic analysis in 13 Japanese families (10 of which were from the northern part of Japan) with sensorineural hearing loss and the 1555A-G mitochondrial mutation. They used data obtained by RFLP and D-loop sequencing of mtDNA. Three families exhibited the same restriction patterns and the same sequence substitution in the D-loop; however, comparison of the 482 basepairs of the D-loop sequence with those of 62 normal Japanese subjects showed that the remaining 10 families were scattered along the phylogenetic tree. This indicated that, except for 3 families, there was no common ancestor for the families bearing the 1555A-G mutation, and that the mutation occurred multiple times in Japan. Pandya et al. (1999) reported 6 unrelated Mongolian deaf students with cosegregation of a homoplasmic 1555A-G mutation and a homoplasmic 7444G-A mutation in the MTCO1 gene (516030.0001). Five of the individuals had a family history consistent with matrilineal transmission of hearing loss. Only 2 individuals had a definite history of aminoglycoside exposure, but all 6 had severe to profound bilateral sensorineural hearing loss detected at birth or in infancy. Santorelli et al. (1999) described the 1555A-G mutation in a 35-year-old woman who had suffered from a restrictive cardiomyopathy from early adulthood, with a family history suggesting maternal transmission, whereas her brother and one of her daughters had transient valvular heart disease in early childhood. The daughters remained at risk for cardiomyopathy, because cardiac symptoms in the proposita did not start until she was in her early twenties and worsened considerably over the course of the next 10 years. Furthermore, both her mother and the maternal grandmother died suddenly in their thirties of cardiac failure. The 1555A-G mutation was present in heteroplasmic state, both in the patient and in her maternal relatives. From phylogenetic analyses of haplotypes and detailed survey of population controls in 50 Spanish and 4 Cuban families with the 1555A-G mutation, Torroni et al. (1999) found that the 1555A-G mutation could be attributed to more than 30 independent mutational events and that it occurred on mtDNA haplogroups that are common in all European populations. This indicated that the relatively high detection rate of this mutation in Spain is not due to sampling biases or to a single major founder event. The results also supported the conclusion that mtDNA backgrounds do not play a significant role in the expression of the 1555A-G mutation. The identification of such a large number of families in Spain, relative to the few detected in other European populations (Casano et al., 1998), had prompted the study. Overall, Torroni et al. (1999) interpreted the findings as indicating that the rare detection of this mutation in other populations is most likely due to inadequacy in patient ascertainment and molecular screening. This probable lack of identification of the 1555A-G mutation in subjects affected by sensorineural hearing loss implies that their maternally related relatives are not benefiting by presymptomatic detection and information concerning their increased risk of ototoxicity due to aminoglycoside treatment. Guan et al. (2000) studied the sensitivity to the aminoglycoside paromomycin in lymphoblastoid cell lines derived from 5 deaf individuals and 5 hearing individuals from an Arab-Israeli family carrying the 1555A-G mutation and 3 married-in controls from the same family. Exposure to a high concentration of paromomycin (2 mg/ml), which caused an 8% average increase in doubling time (DT) in the control cell lines, produced higher average DT increases (49% and 47%) in the A1555G mutation-carrying cell lines derived from symptomatic and asymptomatic individuals, respectively. The ratios of translation rates in the presence and absence of paromomycin, which reflected the effect of the drug on mitochondrial protein synthesis, were significantly decreased in the cell lines derived from symptomatic and asymptomatic individuals, compared to controls. The authors concluded that the A1555G mutation in mitochondrial 12S rRNA results in alteration of mitochondrial protein synthesis in the presence of aminoglycosides, thus reducing the overall translation rate down to and below the minimal level required for normal cellular function (40 to 50%). Bykhovskaya et al. (2000) studied 10 multiplex Spanish and Italian families with 35 members with the 1555A-G mutation and sensorineural deafness. Nonparametric analysis supported the role of the chromosomal region around marker D8S277, with a combined maximized allele-sharing lod score of 3.1 in Arab-Israeli/Spanish/Italian families. Bykhovskaya et al. (2001) obtained 47 DNAs from members of 5 multiplex families from Spain, 1 from Italy, and 1 nuclear family from Finland with matrilineal nonsyndromic hearing loss, showing a combined lod score of 4.0 for the region containing markers D8S277, D8S561, and D8S1819. This finding represented the first identification of a modifier locus for a human mitochondrial DNA disease and supported the concept of mitochondrial DNA diseases having complex inheritance. This modifier gene would be a susceptibility gene and would probably not be sufficient to cause disease in the absence of homoplasmy for the 1555A-G mutation. Finnala and Majamaa (2003) performed fine mapping of the region around marker D8S277 in a large Finnish family with nonsyndromic sensorineural hearing loss, 3 members of which had been part of the study by Bykhovskaya et al. (2001). Haplotype comparison of 9 affected and 7 unaffected persons excluded the region around 8p23 as the site of a susceptibility locus for hearing impairment in this family. Ostergaard et al. (2002) studied 85 Danish patients with varying degrees of hearing impairment and found 2 (2.4%) with the 1555A-G mutation. Neither had received aminoglycosides. Malik et al. (2003) reported a large family of Balinese Indonesian origin with congenital progressive sensorineural deafness associated with the 1555A-G mutation. The pedigree showed a generally maternal inheritance pattern with some exceptions, resulting from an unusual multiple entry of the mutation into the pedigree. A complete mtDNA sequence from 3 Balinese individuals showed a relatively large number of SNPs not previously reported, and confirmed the genetic distance of Southeast Asian populations from those of Caucasians and Japanese. Del Castillo et al. (2003) noted that in most reported cases of nonsyndromic hearing loss associated with the 1555A-G mutation, the mutation was found in homoplasmic state. In 6 Spanish families, they identified the mutation in heteroplasmic state, causing sensorineural hearing loss. The proportion of mutant copies was approximately correlated with the degree of symptoms. Patients carrying less than 20% of mutant copies were asymptomatic or had a mild hearing loss, whereas heteroplasmic patients with more than 52% of mutant copies had moderate to severe hearing loss. Malik et al. (2003) reported a high prevalence (5.3%) of the 1555A-G mutation in sensorineural deafness patients in Indonesia. This supported the need for mutation detection before the administration of aminoglycoside antibiotics in Asian populations. Tekin et al. (2003) screened 168 patients from independent Turkish families (72 simplex and 96 multiplex) with prelingual deafness for the 1555A-G MTRNR1 mutation and the 7445A-G MTTS1 mutation (590080.0002). None of the patients had the 7445A-G mutation, but 3 probands (1.8%) had the 1555A-G mutation. All 3 had been exposed to parenteral antibiotics (possibly aminoglycosides) during the first year of life. A sister of 1 patient was also deaf. The mother, 2 sibs, and a 3-year-old niece of another patient had the 1555A-G mutations with normal hearing, suggesting mitochondrial inheritance and incomplete penetrance. Noguchi et al. (2004) identified the 1555A-G mutation in 1 (1.6%) of 63 Japanese patients with sporadic hearing loss and in 6 (8.0%) of 75 Japanese patients with familial hearing loss. Two (33.3%) of 6 patients presenting with aminoglycoside-induced sensorineural hearing loss had the 1555A-G mutation. All but one of the patients carrying the mutation showed a high-frequency hearing loss, and audiometric studies suggested that the hearing loss was due to impairment of the cochlear hair cells. Yuan et al. (2005) reported cosegregation of a homoplasmic 1555A-G mutation and a homoplasmic 7444G-A MTCO1 mutation in affected members of a Chinese family with aminoglycoside-induced sensorineural hearing loss. One additional family member with both mutations, who had a history of exposure to noise but not to aminoglycoside, exhibited mild hearing impairment. The dose and age at the time of drug administration seemed to be correlated with the severity of the hearing loss. Guan et al. (2006) identified a nuclear modifier gene for 1555A-G deafness: TRMU (610230), which encodes a highly conserved mitochondrial protein related to transfer RNA (tRNA) modification. Genotyping analysis of TRMU in 613 subjects from 1 Arab Israeli kindred, 210 European (Italian and Spanish) families, and 31 Chinese pedigrees carrying the 1555A-G or the 1494C-T (561000.0004) mutation revealed a missense mutation altering an invariant amino acid residue in the evolutionarily conserved N-terminal region of the TRMU protein (A10S; 610230.0001). All 18 Arab-Israeli/Italian-Spanish matrilineal relatives carrying both the TRMU A10S and the 12S rRNA and the 1555A-G mutations exhibited prelingual profound deafness. Functional analysis showed that this mutation did not affect importation of TRMU precursors into mitochondria. However, the homozygous A10S mutation led to a marked failure in mitochondrial tRNA metabolisms, specifically reducing the steady-state levels of mitochondrial tRNA. As a consequence, these defects contribute to the impairment of mitochondrial protein synthesis. The resultant biochemical defects aggravate the mitochondrial dysfunction associated with the A1555G mutation, exceeding the threshold for expressing the deafness phenotype. These findings indicated that the mutated TRMU, acting as a modifier factor, modulates the phenotypic manifestation of the deafness-associated 12S rRNA mutations. Using molecular dynamic simulations, Meng et al. (2017) showed that the A10S mutation introduced a ser10 dynamic electrostatic interaction with lys106 in helix-4 of the TRMU catalytic domain. Western blot analysis revealed reduced levels of TRMU in cells with the A10S mutation, and thermal shift analysis showed that the Tm value of the mutant TRMU protein was lower than wildtype. The A10S mutation also caused marked decreases in 2-thiouridine modification of U34 in tRNAs for lys (MTTK; 590060), glu (MTTE; 590025), and gln (MTTQ; 590030), while mildly increasing the aminoacylated efficiency of the tRNAs. The altered 2-thiouridine modification worsened the impairment of mitochondrial translocation associated with the MTRNR1 1555A-G mutation. Defective translation resulted in reduced activity in mitochondrial respiration chains, leading to reduction of mitochondrial ATP production and elevated production of reactive oxidative species. Thus, the A10S mutation in TRMU worsened the mitochondrial dysfunction associated with the 1555A-G mutation, exceeding the threshold for expressing the deafness phenotype. In 4 and 16 Chinese pedigrees with aminoglycoside-induced and nonsyndromic hearing impairment, Young et al. (2005) and Dai et al. (2006), respectively, found extremely low penetrance of hearing loss, with an average of 8% for both studies. Mutational analysis showed the presence of homoplasmic 1555A-G mutations. The low penetrance in these families, particularly compared with other pedigrees, suggested that the 1555A-G mutation itself is not sufficient to produce the clinical phenotype. In 443 Spanish families and sporadic patients with hearing impairment, Ballana et al. (2006) found the 1555A-G mutation in 69 (15%) families and sporadic patients. The mutation was not fully penetrant as only 63% of individuals with the mutation had developed hearing impairment. They determined that the 1555A-G mutation is predicted to change the RNA secondary structure. Among 24 carriers of the 1555A-G mutation from 9 Spanish families, Bravo et al. (2006) found a wide phenotypic range. Six had normal hearing, and 18 had mild to profound hearing loss most severe at high frequencies. The age at onset ranged from 1 to 20 years. Four individuals with moderate to profound hearing loss had aminoglycoside-induced deafness. Tinnitus was reported by 9 deaf and 2 hearing individuals, and 2 deaf individuals reported dizziness. All with deafness had absent otoacoustic emissions with normal auditory brainstem responses, suggesting dysfunction of the outer hair cells of the cochlea. Two normal hearing individuals had subclinical alterations of the acoustic reflexes at high frequencies. Bravo et al. (2006) stated that the findings were consistent with a model in which a defect in mitochondrial translation of ribosomes results in a decline of ATP production and an increase in reactive oxygen species, resulting in hair cell apoptosis. Tang et al. (2007) reported 7 Han Chinese families with aminoglycoside-induced and nonsyndromic bilateral hearing loss due to the 1555A-G mutation. The penetrance of hearing loss in these pedigrees ranged from 3 to 29%, with an average of 13.6%, when aminoglycoside-induced deafness was included. When the effect of aminoglycosides was excluded, the penetrances of hearing loss ranged from 0 to 17%, with an average of 5.3%. Haplotype analysis suggested that the A1555G mutation occurred sporadically and multiplied through evolution of the mtDNA in China. Tang et al. (2007) concluded that aminoglycoside exposure appears to be a major modifier factor for the phenotypic manifestation of the A1555G mutation in these Chinese families. Dai et al. (2008) reported a Chinese girl with onset of profound nonsyndromic hearing loss at age 6 months who had both the 1555A-G and 1095T-C (561000.0003) mutations. The authors suggested that the 2 mutations acted together to enhance the biochemical defects resulting in hearing impairment. (less)

In patients from 3 unrelated families with familial aminoglycoside-induced deafness (580000) and in a large Arab Israeli pedigree with nonsyndromic deafness (500008), Prezant et al. (1993) found a 1555A-G transition in the 12S rRNA gene (MTRNR1), a site implicated in aminoglycoside activity by analogy to the evolutionarily related bacterial ribosome. Hutchin et al. (1993) found the same mutation in 2 Japanese pedigrees and 3 Chinese pedigrees with aminoglycoside-induced deafness and in 4 of 74 sporadic deafness cases thought to be the result of exposure to aminoglycosides. The frequency of the mutation in the hearing population was less than 1 in 200. The 1555A-G mutation was inferred to create a new basepair at the terminus of the penultimate helix of the 12S RNA. Hutchin et al. (1993) proposed that this additional basepair decreases the molecular volume taken up by RNA at this site relative to the unpaired bases, thus increasing the size of the aminoglycoside binding pocket and making aminoglycoside binding tighter. Pandya et al. (1997) ascertained 3 Mongolian pedigrees from a school for the deaf and blind, which contained multiple affected subjects with streptomycin-induced deafness in a pattern consistent with matrilineal transmission. In 2 of the 3 families they found the 1555A-G mutation in the 12S rRNA gene by restriction analysis as well as by direct sequencing. No other example of this substitution was found among 400 control samples from Mongolians with normal hearing. In countries where aminoglycosides are widely used, genetic counseling and screening of high-risk families before the use of these drugs could have a dramatic effect on the incidence of deafness. Gardner et al. (1997) reported the 1555A-G point mutation in the 12S ribosomal RNA gene in a South African family with streptomycin-induced sensorineural deafness. They came to the same conclusions as Pandya et al. (1997) regarding the usefulness of genetic counseling and screening of high-risk families in countries where aminoglycosides are widely used. Estivill et al. (1998) studied 70 Spanish families with sensorineural deafness (36 congenital and 34 late-onset) for the mtDNA 1555A-G mutation. The mutation was found in 19 families with maternally transmitted deafness but not in the other 51 families or in 200 control subjects. In 12 families, all the patients with the 1555A-G mutation who received aminoglycosides became deaf, representing 30.3% of the deaf patients in these families. None of the deaf patients from 7 other families received aminoglycosides. Overall, only 17.7% of the patients with deafness and the 1555A-G mutation had been treated with aminoglycosides. The age at onset of deafness was lower (median age 5 years, range 1 to 52 years) in those treated with aminoglycosides than in those who did not receive aminoglycosides (median age 20 years, range 1 to 65 years). The mtDNA of these families belonged to haplotypes common in Europeans. Data indicated that the 1555A-G mutation accounts for a large proportion of the Spanish families with late-onset sensorineural deafness, that the 1555A-G mutation has an age-dependent penetrance for deafness (enhanced by treatment with aminoglycosides), and that mtDNA backgrounds probably do not play a major role in disease expression. Abe et al. (1998) performed a phylogenetic analysis in 13 Japanese families (10 of which were from the northern part of Japan) with sensorineural hearing loss and the 1555A-G mitochondrial mutation. They used data obtained by RFLP and D-loop sequencing of mtDNA. Three families exhibited the same restriction patterns and the same sequence substitution in the D-loop; however, comparison of the 482 basepairs of the D-loop sequence with those of 62 normal Japanese subjects showed that the remaining 10 families were scattered along the phylogenetic tree. This indicated that, except for 3 families, there was no common ancestor for the families bearing the 1555A-G mutation, and that the mutation occurred multiple times in Japan. Pandya et al. (1999) reported 6 unrelated Mongolian deaf students with cosegregation of a homoplasmic 1555A-G mutation and a homoplasmic 7444G-A mutation in the MTCO1 gene (516030.0001). Five of the individuals had a family history consistent with matrilineal transmission of hearing loss. Only 2 individuals had a definite history of aminoglycoside exposure, but all 6 had severe to profound bilateral sensorineural hearing loss detected at birth or in infancy. Santorelli et al. (1999) described the 1555A-G mutation in a 35-year-old woman who had suffered from a restrictive cardiomyopathy from early adulthood, with a family history suggesting maternal transmission, whereas her brother and one of her daughters had transient valvular heart disease in early childhood. The daughters remained at risk for cardiomyopathy, because cardiac symptoms in the proposita did not start until she was in her early twenties and worsened considerably over the course of the next 10 years. Furthermore, both her mother and the maternal grandmother died suddenly in their thirties of cardiac failure. The 1555A-G mutation was present in heteroplasmic state, both in the patient and in her maternal relatives. From phylogenetic analyses of haplotypes and detailed survey of population controls in 50 Spanish and 4 Cuban families with the 1555A-G mutation, Torroni et al. (1999) found that the 1555A-G mutation could be attributed to more than 30 independent mutational events and that it occurred on mtDNA haplogroups that are common in all European populations. This indicated that the relatively high detection rate of this mutation in Spain is not due to sampling biases or to a single major founder event. The results also supported the conclusion that mtDNA backgrounds do not play a significant role in the expression of the 1555A-G mutation. The identification of such a large number of families in Spain, relative to the few detected in other European populations (Casano et al., 1998), had prompted the study. Overall, Torroni et al. (1999) interpreted the findings as indicating that the rare detection of this mutation in other populations is most likely due to inadequacy in patient ascertainment and molecular screening. This probable lack of identification of the 1555A-G mutation in subjects affected by sensorineural hearing loss implies that their maternally related relatives are not benefiting by presymptomatic detection and information concerning their increased risk of ototoxicity due to aminoglycoside treatment. Guan et al. (2000) studied the sensitivity to the aminoglycoside paromomycin in lymphoblastoid cell lines derived from 5 deaf individuals and 5 hearing individuals from an Arab-Israeli family carrying the 1555A-G mutation and 3 married-in controls from the same family. Exposure to a high concentration of paromomycin (2 mg/ml), which caused an 8% average increase in doubling time (DT) in the control cell lines, produced higher average DT increases (49% and 47%) in the A1555G mutation-carrying cell lines derived from symptomatic and asymptomatic individuals, respectively. The ratios of translation rates in the presence and absence of paromomycin, which reflected the effect of the drug on mitochondrial protein synthesis, were significantly decreased in the cell lines derived from symptomatic and asymptomatic individuals, compared to controls. The authors concluded that the A1555G mutation in mitochondrial 12S rRNA results in alteration of mitochondrial protein synthesis in the presence of aminoglycosides, thus reducing the overall translation rate down to and below the minimal level required for normal cellular function (40 to 50%). Bykhovskaya et al. (2000) studied 10 multiplex Spanish and Italian families with 35 members with the 1555A-G mutation and sensorineural deafness. Nonparametric analysis supported the role of the chromosomal region around marker D8S277, with a combined maximized allele-sharing lod score of 3.1 in Arab-Israeli/Spanish/Italian families. Bykhovskaya et al. (2001) obtained 47 DNAs from members of 5 multiplex families from Spain, 1 from Italy, and 1 nuclear family from Finland with matrilineal nonsyndromic hearing loss, showing a combined lod score of 4.0 for the region containing markers D8S277, D8S561, and D8S1819. This finding represented the first identification of a modifier locus for a human mitochondrial DNA disease and supported the concept of mitochondrial DNA diseases having complex inheritance. This modifier gene would be a susceptibility gene and would probably not be sufficient to cause disease in the absence of homoplasmy for the 1555A-G mutation. Finnala and Majamaa (2003) performed fine mapping of the region around marker D8S277 in a large Finnish family with nonsyndromic sensorineural hearing loss, 3 members of which had been part of the study by Bykhovskaya et al. (2001). Haplotype comparison of 9 affected and 7 unaffected persons excluded the region around 8p23 as the site of a susceptibility locus for hearing impairment in this family. Ostergaard et al. (2002) studied 85 Danish patients with varying degrees of hearing impairment and found 2 (2.4%) with the 1555A-G mutation. Neither had received aminoglycosides. Malik et al. (2003) reported a large family of Balinese Indonesian origin with congenital progressive sensorineural deafness associated with the 1555A-G mutation. The pedigree showed a generally maternal inheritance pattern with some exceptions, resulting from an unusual multiple entry of the mutation into the pedigree. A complete mtDNA sequence from 3 Balinese individuals showed a relatively large number of SNPs not previously reported, and confirmed the genetic distance of Southeast Asian populations from those of Caucasians and Japanese. Del Castillo et al. (2003) noted that in most reported cases of nonsyndromic hearing loss associated with the 1555A-G mutation, the mutation was found in homoplasmic state. In 6 Spanish families, they identified the mutation in heteroplasmic state, causing sensorineural hearing loss. The proportion of mutant copies was approximately correlated with the degree of symptoms. Patients carrying less than 20% of mutant copies were asymptomatic or had a mild hearing loss, whereas heteroplasmic patients with more than 52% of mutant copies had moderate to severe hearing loss. Malik et al. (2003) reported a high prevalence (5.3%) of the 1555A-G mutation in sensorineural deafness patients in Indonesia. This supported the need for mutation detection before the administration of aminoglycoside antibiotics in Asian populations. Tekin et al. (2003) screened 168 patients from independent Turkish families (72 simplex and 96 multiplex) with prelingual deafness for the 1555A-G MTRNR1 mutation and the 7445A-G MTTS1 mutation (590080.0002). None of the patients had the 7445A-G mutation, but 3 probands (1.8%) had the 1555A-G mutation. All 3 had been exposed to parenteral antibiotics (possibly aminoglycosides) during the first year of life. A sister of 1 patient was also deaf. The mother, 2 sibs, and a 3-year-old niece of another patient had the 1555A-G mutations with normal hearing, suggesting mitochondrial inheritance and incomplete penetrance. Noguchi et al. (2004) identified the 1555A-G mutation in 1 (1.6%) of 63 Japanese patients with sporadic hearing loss and in 6 (8.0%) of 75 Japanese patients with familial hearing loss. Two (33.3%) of 6 patients presenting with aminoglycoside-induced sensorineural hearing loss had the 1555A-G mutation. All but one of the patients carrying the mutation showed a high-frequency hearing loss, and audiometric studies suggested that the hearing loss was due to impairment of the cochlear hair cells. Yuan et al. (2005) reported cosegregation of a homoplasmic 1555A-G mutation and a homoplasmic 7444G-A MTCO1 mutation in affected members of a Chinese family with aminoglycoside-induced sensorineural hearing loss. One additional family member with both mutations, who had a history of exposure to noise but not to aminoglycoside, exhibited mild hearing impairment. The dose and age at the time of drug administration seemed to be correlated with the severity of the hearing loss. Guan et al. (2006) identified a nuclear modifier gene for 1555A-G deafness: TRMU (610230), which encodes a highly conserved mitochondrial protein related to transfer RNA (tRNA) modification. Genotyping analysis of TRMU in 613 subjects from 1 Arab Israeli kindred, 210 European (Italian and Spanish) families, and 31 Chinese pedigrees carrying the 1555A-G or the 1494C-T (561000.0004) mutation revealed a missense mutation altering an invariant amino acid residue in the evolutionarily conserved N-terminal region of the TRMU protein (A10S; 610230.0001). All 18 Arab-Israeli/Italian-Spanish matrilineal relatives carrying both the TRMU A10S and the 12S rRNA and the 1555A-G mutations exhibited prelingual profound deafness. Functional analysis showed that this mutation did not affect importation of TRMU precursors into mitochondria. However, the homozygous A10S mutation led to a marked failure in mitochondrial tRNA metabolisms, specifically reducing the steady-state levels of mitochondrial tRNA. As a consequence, these defects contribute to the impairment of mitochondrial protein synthesis. The resultant biochemical defects aggravate the mitochondrial dysfunction associated with the A1555G mutation, exceeding the threshold for expressing the deafness phenotype. These findings indicated that the mutated TRMU, acting as a modifier factor, modulates the phenotypic manifestation of the deafness-associated 12S rRNA mutations. Using molecular dynamic simulations, Meng et al. (2017) showed that the A10S mutation introduced a ser10 dynamic electrostatic interaction with lys106 in helix-4 of the TRMU catalytic domain. Western blot analysis revealed reduced levels of TRMU in cells with the A10S mutation, and thermal shift analysis showed that the Tm value of the mutant TRMU protein was lower than wildtype. The A10S mutation also caused marked decreases in 2-thiouridine modification of U34 in tRNAs for lys (MTTK; 590060), glu (MTTE; 590025), and gln (MTTQ; 590030), while mildly increasing the aminoacylated efficiency of the tRNAs. The altered 2-thiouridine modification worsened the impairment of mitochondrial translocation associated with the MTRNR1 1555A-G mutation. Defective translation resulted in reduced activity in mitochondrial respiration chains, leading to reduction of mitochondrial ATP production and elevated production of reactive oxidative species. Thus, the A10S mutation in TRMU worsened the mitochondrial dysfunction associated with the 1555A-G mutation, exceeding the threshold for expressing the deafness phenotype. In 4 and 16 Chinese pedigrees with aminoglycoside-induced and nonsyndromic hearing impairment, Young et al. (2005) and Dai et al. (2006), respectively, found extremely low penetrance of hearing loss, with an average of 8% for both studies. Mutational analysis showed the presence of homoplasmic 1555A-G mutations. The low penetrance in these families, particularly compared with other pedigrees, suggested that the 1555A-G mutation itself is not sufficient to produce the clinical phenotype. In 443 Spanish families and sporadic patients with hearing impairment, Ballana et al. (2006) found the 1555A-G mutation in 69 (15%) families and sporadic patients. The mutation was not fully penetrant as only 63% of individuals with the mutation had developed hearing impairment. They determined that the 1555A-G mutation is predicted to change the RNA secondary structure. Among 24 carriers of the 1555A-G mutation from 9 Spanish families, Bravo et al. (2006) found a wide phenotypic range. Six had normal hearing, and 18 had mild to profound hearing loss most severe at high frequencies. The age at onset ranged from 1 to 20 years. Four individuals with moderate to profound hearing loss had aminoglycoside-induced deafness. Tinnitus was reported by 9 deaf and 2 hearing individuals, and 2 deaf individuals reported dizziness. All with deafness had absent otoacoustic emissions with normal auditory brainstem responses, suggesting dysfunction of the outer hair cells of the cochlea. Two normal hearing individuals had subclinical alterations of the acoustic reflexes at high frequencies. Bravo et al. (2006) stated that the findings were consistent with a model in which a defect in mitochondrial translation of ribosomes results in a decline of ATP production and an increase in reactive oxygen species, resulting in hair cell apoptosis. Tang et al. (2007) reported 7 Han Chinese families with aminoglycoside-induced and nonsyndromic bilateral hearing loss due to the 1555A-G mutation. The penetrance of hearing loss in these pedigrees ranged from 3 to 29%, with an average of 13.6%, when aminoglycoside-induced deafness was included. When the effect of aminoglycosides was excluded, the penetrances of hearing loss ranged from 0 to 17%, with an average of 5.3%. Haplotype analysis suggested that the A1555G mutation occurred sporadically and multiplied through evolution of the mtDNA in China. Tang et al. (2007) concluded that aminoglycoside exposure appears to be a major modifier factor for the phenotypic manifestation of the A1555G mutation in these Chinese families. Dai et al. (2008) reported a Chinese girl with onset of profound nonsyndromic hearing loss at age 6 months who had both the 1555A-G and 1095T-C (561000.0003) mutations. The authors suggested that the 2 mutations acted together to enhance the biochemical defects resulting in hearing impairment. (less)

In patients from 3 unrelated families with familial aminoglycoside-induced deafness (580000) and in a large Arab Israeli pedigree with nonsyndromic deafness (500008), Prezant et al. (1993) found a 1555A-G transition in the 12S rRNA gene (MTRNR1), a site implicated in aminoglycoside activity by analogy to the evolutionarily related bacterial ribosome. Hutchin et al. (1993) found the same mutation in 2 Japanese pedigrees and 3 Chinese pedigrees with aminoglycoside-induced deafness and in 4 of 74 sporadic deafness cases thought to be the result of exposure to aminoglycosides. The frequency of the mutation in the hearing population was less than 1 in 200. The 1555A-G mutation was inferred to create a new basepair at the terminus of the penultimate helix of the 12S RNA. Hutchin et al. (1993) proposed that this additional basepair decreases the molecular volume taken up by RNA at this site relative to the unpaired bases, thus increasing the size of the aminoglycoside binding pocket and making aminoglycoside binding tighter. Pandya et al. (1997) ascertained 3 Mongolian pedigrees from a school for the deaf and blind, which contained multiple affected subjects with streptomycin-induced deafness in a pattern consistent with matrilineal transmission. In 2 of the 3 families they found the 1555A-G mutation in the 12S rRNA gene by restriction analysis as well as by direct sequencing. No other example of this substitution was found among 400 control samples from Mongolians with normal hearing. In countries where aminoglycosides are widely used, genetic counseling and screening of high-risk families before the use of these drugs could have a dramatic effect on the incidence of deafness. Gardner et al. (1997) reported the 1555A-G point mutation in the 12S ribosomal RNA gene in a South African family with streptomycin-induced sensorineural deafness. They came to the same conclusions as Pandya et al. (1997) regarding the usefulness of genetic counseling and screening of high-risk families in countries where aminoglycosides are widely used. Estivill et al. (1998) studied 70 Spanish families with sensorineural deafness (36 congenital and 34 late-onset) for the mtDNA 1555A-G mutation. The mutation was found in 19 families with maternally transmitted deafness but not in the other 51 families or in 200 control subjects. In 12 families, all the patients with the 1555A-G mutation who received aminoglycosides became deaf, representing 30.3% of the deaf patients in these families. None of the deaf patients from 7 other families received aminoglycosides. Overall, only 17.7% of the patients with deafness and the 1555A-G mutation had been treated with aminoglycosides. The age at onset of deafness was lower (median age 5 years, range 1 to 52 years) in those treated with aminoglycosides than in those who did not receive aminoglycosides (median age 20 years, range 1 to 65 years). The mtDNA of these families belonged to haplotypes common in Europeans. Data indicated that the 1555A-G mutation accounts for a large proportion of the Spanish families with late-onset sensorineural deafness, that the 1555A-G mutation has an age-dependent penetrance for deafness (enhanced by treatment with aminoglycosides), and that mtDNA backgrounds probably do not play a major role in disease expression. Abe et al. (1998) performed a phylogenetic analysis in 13 Japanese families (10 of which were from the northern part of Japan) with sensorineural hearing loss and the 1555A-G mitochondrial mutation. They used data obtained by RFLP and D-loop sequencing of mtDNA. Three families exhibited the same restriction patterns and the same sequence substitution in the D-loop; however, comparison of the 482 basepairs of the D-loop sequence with those of 62 normal Japanese subjects showed that the remaining 10 families were scattered along the phylogenetic tree. This indicated that, except for 3 families, there was no common ancestor for the families bearing the 1555A-G mutation, and that the mutation occurred multiple times in Japan. Pandya et al. (1999) reported 6 unrelated Mongolian deaf students with cosegregation of a homoplasmic 1555A-G mutation and a homoplasmic 7444G-A mutation in the MTCO1 gene (516030.0001). Five of the individuals had a family history consistent with matrilineal transmission of hearing loss. Only 2 individuals had a definite history of aminoglycoside exposure, but all 6 had severe to profound bilateral sensorineural hearing loss detected at birth or in infancy. Santorelli et al. (1999) described the 1555A-G mutation in a 35-year-old woman who had suffered from a restrictive cardiomyopathy from early adulthood, with a family history suggesting maternal transmission, whereas her brother and one of her daughters had transient valvular heart disease in early childhood. The daughters remained at risk for cardiomyopathy, because cardiac symptoms in the proposita did not start until she was in her early twenties and worsened considerably over the course of the next 10 years. Furthermore, both her mother and the maternal grandmother died suddenly in their thirties of cardiac failure. The 1555A-G mutation was present in heteroplasmic state, both in the patient and in her maternal relatives. From phylogenetic analyses of haplotypes and detailed survey of population controls in 50 Spanish and 4 Cuban families with the 1555A-G mutation, Torroni et al. (1999) found that the 1555A-G mutation could be attributed to more than 30 independent mutational events and that it occurred on mtDNA haplogroups that are common in all European populations. This indicated that the relatively high detection rate of this mutation in Spain is not due to sampling biases or to a single major founder event. The results also supported the conclusion that mtDNA backgrounds do not play a significant role in the expression of the 1555A-G mutation. The identification of such a large number of families in Spain, relative to the few detected in other European populations (Casano et al., 1998), had prompted the study. Overall, Torroni et al. (1999) interpreted the findings as indicating that the rare detection of this mutation in other populations is most likely due to inadequacy in patient ascertainment and molecular screening. This probable lack of identification of the 1555A-G mutation in subjects affected by sensorineural hearing loss implies that their maternally related relatives are not benefiting by presymptomatic detection and information concerning their increased risk of ototoxicity due to aminoglycoside treatment. Guan et al. (2000) studied the sensitivity to the aminoglycoside paromomycin in lymphoblastoid cell lines derived from 5 deaf individuals and 5 hearing individuals from an Arab-Israeli family carrying the 1555A-G mutation and 3 married-in controls from the same family. Exposure to a high concentration of paromomycin (2 mg/ml), which caused an 8% average increase in doubling time (DT) in the control cell lines, produced higher average DT increases (49% and 47%) in the A1555G mutation-carrying cell lines derived from symptomatic and asymptomatic individuals, respectively. The ratios of translation rates in the presence and absence of paromomycin, which reflected the effect of the drug on mitochondrial protein synthesis, were significantly decreased in the cell lines derived from symptomatic and asymptomatic individuals, compared to controls. The authors concluded that the A1555G mutation in mitochondrial 12S rRNA results in alteration of mitochondrial protein synthesis in the presence of aminoglycosides, thus reducing the overall translation rate down to and below the minimal level required for normal cellular function (40 to 50%). Bykhovskaya et al. (2000) studied 10 multiplex Spanish and Italian families with 35 members with the 1555A-G mutation and sensorineural deafness. Nonparametric analysis supported the role of the chromosomal region around marker D8S277, with a combined maximized allele-sharing lod score of 3.1 in Arab-Israeli/Spanish/Italian families. Bykhovskaya et al. (2001) obtained 47 DNAs from members of 5 multiplex families from Spain, 1 from Italy, and 1 nuclear family from Finland with matrilineal nonsyndromic hearing loss, showing a combined lod score of 4.0 for the region containing markers D8S277, D8S561, and D8S1819. This finding represented the first identification of a modifier locus for a human mitochondrial DNA disease and supported the concept of mitochondrial DNA diseases having complex inheritance. This modifier gene would be a susceptibility gene and would probably not be sufficient to cause disease in the absence of homoplasmy for the 1555A-G mutation. Finnala and Majamaa (2003) performed fine mapping of the region around marker D8S277 in a large Finnish family with nonsyndromic sensorineural hearing loss, 3 members of which had been part of the study by Bykhovskaya et al. (2001). Haplotype comparison of 9 affected and 7 unaffected persons excluded the region around 8p23 as the site of a susceptibility locus for hearing impairment in this family. Ostergaard et al. (2002) studied 85 Danish patients with varying degrees of hearing impairment and found 2 (2.4%) with the 1555A-G mutation. Neither had received aminoglycosides. Malik et al. (2003) reported a large family of Balinese Indonesian origin with congenital progressive sensorineural deafness associated with the 1555A-G mutation. The pedigree showed a generally maternal inheritance pattern with some exceptions, resulting from an unusual multiple entry of the mutation into the pedigree. A complete mtDNA sequence from 3 Balinese individuals showed a relatively large number of SNPs not previously reported, and confirmed the genetic distance of Southeast Asian populations from those of Caucasians and Japanese. Del Castillo et al. (2003) noted that in most reported cases of nonsyndromic hearing loss associated with the 1555A-G mutation, the mutation was found in homoplasmic state. In 6 Spanish families, they identified the mutation in heteroplasmic state, causing sensorineural hearing loss. The proportion of mutant copies was approximately correlated with the degree of symptoms. Patients carrying less than 20% of mutant copies were asymptomatic or had a mild hearing loss, whereas heteroplasmic patients with more than 52% of mutant copies had moderate to severe hearing loss. Malik et al. (2003) reported a high prevalence (5.3%) of the 1555A-G mutation in sensorineural deafness patients in Indonesia. This supported the need for mutation detection before the administration of aminoglycoside antibiotics in Asian populations. Tekin et al. (2003) screened 168 patients from independent Turkish families (72 simplex and 96 multiplex) with prelingual deafness for the 1555A-G MTRNR1 mutation and the 7445A-G MTTS1 mutation (590080.0002). None of the patients had the 7445A-G mutation, but 3 probands (1.8%) had the 1555A-G mutation. All 3 had been exposed to parenteral antibiotics (possibly aminoglycosides) during the first year of life. A sister of 1 patient was also deaf. The mother, 2 sibs, and a 3-year-old niece of another patient had the 1555A-G mutations with normal hearing, suggesting mitochondrial inheritance and incomplete penetrance. Noguchi et al. (2004) identified the 1555A-G mutation in 1 (1.6%) of 63 Japanese patients with sporadic hearing loss and in 6 (8.0%) of 75 Japanese patients with familial hearing loss. Two (33.3%) of 6 patients presenting with aminoglycoside-induced sensorineural hearing loss had the 1555A-G mutation. All but one of the patients carrying the mutation showed a high-frequency hearing loss, and audiometric studies suggested that the hearing loss was due to impairment of the cochlear hair cells. Yuan et al. (2005) reported cosegregation of a homoplasmic 1555A-G mutation and a homoplasmic 7444G-A MTCO1 mutation in affected members of a Chinese family with aminoglycoside-induced sensorineural hearing loss. One additional family member with both mutations, who had a history of exposure to noise but not to aminoglycoside, exhibited mild hearing impairment. The dose and age at the time of drug administration seemed to be correlated with the severity of the hearing loss. Guan et al. (2006) identified a nuclear modifier gene for 1555A-G deafness: TRMU (610230), which encodes a highly conserved mitochondrial protein related to transfer RNA (tRNA) modification. Genotyping analysis of TRMU in 613 subjects from 1 Arab Israeli kindred, 210 European (Italian and Spanish) families, and 31 Chinese pedigrees carrying the 1555A-G or the 1494C-T (561000.0004) mutation revealed a missense mutation altering an invariant amino acid residue in the evolutionarily conserved N-terminal region of the TRMU protein (A10S; 610230.0001). All 18 Arab-Israeli/Italian-Spanish matrilineal relatives carrying both the TRMU A10S and the 12S rRNA and the 1555A-G mutations exhibited prelingual profound deafness. Functional analysis showed that this mutation did not affect importation of TRMU precursors into mitochondria. However, the homozygous A10S mutation led to a marked failure in mitochondrial tRNA metabolisms, specifically reducing the steady-state levels of mitochondrial tRNA. As a consequence, these defects contribute to the impairment of mitochondrial protein synthesis. The resultant biochemical defects aggravate the mitochondrial dysfunction associated with the A1555G mutation, exceeding the threshold for expressing the deafness phenotype. These findings indicated that the mutated TRMU, acting as a modifier factor, modulates the phenotypic manifestation of the deafness-associated 12S rRNA mutations. Using molecular dynamic simulations, Meng et al. (2017) showed that the A10S mutation introduced a ser10 dynamic electrostatic interaction with lys106 in helix-4 of the TRMU catalytic domain. Western blot analysis revealed reduced levels of TRMU in cells with the A10S mutation, and thermal shift analysis showed that the Tm value of the mutant TRMU protein was lower than wildtype. The A10S mutation also caused marked decreases in 2-thiouridine modification of U34 in tRNAs for lys (MTTK; 590060), glu (MTTE; 590025), and gln (MTTQ; 590030), while mildly increasing the aminoacylated efficiency of the tRNAs. The altered 2-thiouridine modification worsened the impairment of mitochondrial translocation associated with the MTRNR1 1555A-G mutation. Defective translation resulted in reduced activity in mitochondrial respiration chains, leading to reduction of mitochondrial ATP production and elevated production of reactive oxidative species. Thus, the A10S mutation in TRMU worsened the mitochondrial dysfunction associated with the 1555A-G mutation, exceeding the threshold for expressing the deafness phenotype. In 4 and 16 Chinese pedigrees with aminoglycoside-induced and nonsyndromic hearing impairment, Young et al. (2005) and Dai et al. (2006), respectively, found extremely low penetrance of hearing loss, with an average of 8% for both studies. Mutational analysis showed the presence of homoplasmic 1555A-G mutations. The low penetrance in these families, particularly compared with other pedigrees, suggested that the 1555A-G mutation itself is not sufficient to produce the clinical phenotype. In 443 Spanish families and sporadic patients with hearing impairment, Ballana et al. (2006) found the 1555A-G mutation in 69 (15%) families and sporadic patients. The mutation was not fully penetrant as only 63% of individuals with the mutation had developed hearing impairment. They determined that the 1555A-G mutation is predicted to change the RNA secondary structure. Among 24 carriers of the 1555A-G mutation from 9 Spanish families, Bravo et al. (2006) found a wide phenotypic range. Six had normal hearing, and 18 had mild to profound hearing loss most severe at high frequencies. The age at onset ranged from 1 to 20 years. Four individuals with moderate to profound hearing loss had aminoglycoside-induced deafness. Tinnitus was reported by 9 deaf and 2 hearing individuals, and 2 deaf individuals reported dizziness. All with deafness had absent otoacoustic emissions with normal auditory brainstem responses, suggesting dysfunction of the outer hair cells of the cochlea. Two normal hearing individuals had subclinical alterations of the acoustic reflexes at high frequencies. Bravo et al. (2006) stated that the findings were consistent with a model in which a defect in mitochondrial translation of ribosomes results in a decline of ATP production and an increase in reactive oxygen species, resulting in hair cell apoptosis. Tang et al. (2007) reported 7 Han Chinese families with aminoglycoside-induced and nonsyndromic bilateral hearing loss due to the 1555A-G mutation. The penetrance of hearing loss in these pedigrees ranged from 3 to 29%, with an average of 13.6%, when aminoglycoside-induced deafness was included. When the effect of aminoglycosides was excluded, the penetrances of hearing loss ranged from 0 to 17%, with an average of 5.3%. Haplotype analysis suggested that the A1555G mutation occurred sporadically and multiplied through evolution of the mtDNA in China. Tang et al. (2007) concluded that aminoglycoside exposure appears to be a major modifier factor for the phenotypic manifestation of the A1555G mutation in these Chinese families. Dai et al. (2008) reported a Chinese girl with onset of profound nonsyndromic hearing loss at age 6 months who had both the 1555A-G and 1095T-C (561000.0003) mutations. The authors suggested that the 2 mutations acted together to enhance the biochemical defects resulting in hearing impairment. (less)