ClinVar Genomic variation as it relates to human health

Progressive extrapyramidal movement disorder (present) , Progressive spasticity (present) , Elevated brain lactate level by MRS (present) , Symmetric lesions of the basal ganglia (present) , Abnormal circulating creatine kinase concentration (present) , Abnormal circulating lactate dehydrogenase concentration (present) (less)

Gait disturbance (present) , Tremor (present) , Nausea and vomiting (present) , Central hypothyroidism (present) , Episodic vomiting (present) , Hypothyroidism (present) , Episodic hemiplegia (present) , Hypotonia (present) , Microcephaly (present) , Cerebellar ataxia (present) (less)

The allele changes the highly conserved arginine at amino acid 340 to a histidine (R340H). This allele accounts for over 50% of Leber hereditary optic neuropathy (LHON; 535000) cases among Caucasians and over 90% of the cases in Asians. The mutation has not been observed in random population controls, may be either homoplasmic or heteroplasmic within families, and has been shown to have arisen multiple times on different mtDNA haplotypes in association with the disease (Wallace et al., 1988; Singh et al., 1989). In families harboring this mutation, approximately 33 to 60% of the maternal relatives are affected and of these, about 80% are males. Visual recovery is seen in only 4% of cases (see LHON Table, MIM11 foreword section) (Bolhuis et al., 1990; Carducci et al., 1991; Cavelier et al., 1993; Cortelli et al., 1991; Cullom et al., 1993; Erickson and Castora, 1993; Hiida et al., 1991, 1992; Holt et al., 1989; Hotta et al., 1989; Howell et al., 1992; Huoponen et al., 1990; Isashiki and Nakagawa, 1991; Johns, 1990; Johns and Berman, 1991; Johns et al., 1992, 1993; Kormann et al., 1991; Larsson et al., 1991; Lott et al., 1990; Majander et al., 1991; Mashima et al., 1992, 1993; Moorman et al., 1993; Nakamura et al., 1993; Newman, 1993; Newman et al., 1991; Newman and Wallace, 1990; Norby, 1993; Poulton et al., 1991; Singh et al., 1989; Smith et al., 1993; Stone et al., 1990, 1992; Sudoyo et al., 1992; Vilkki et al., 1989, 1990; Wallace et al., 1988; Weiner et al., 1993; Yoneda et al., 1989; Zhu et al., 1992). In 37 Italian subjects with LHON, Torroni et al. (1997) found that 28 were 11778-positive, 7 were 3460-positive (516000.0001) and 2 were 14484-positive (516006.0001). High-resolution restriction endonuclease analysis was also performed in all subjects in order to define the phylogenetic relationships between mtDNA haplotypes and LHON mutations. Ninety-nine Italian controls were screened for mutations and haplotypes. The analysis showed that the putative secondary/intermediate LHON mutations 4216, 4917, 13708, 15257, and 15812 are ancient polymorphisms, are associated in specific combinations, and define 2 common Caucasoid-specific haplotype groupings, designated haplogroups J and T. On the contrary, the same analysis showed that the primary mutations 11778, 3460, and 14484 are recent and are due to multiple mutational events. However, phylogenetic analysis revealed a different evolutionary pattern for the 3 primary mutations. The 3460 mutations were distributed randomly along with phylogenetic trees, without any preferential association with the 9 haplotypes that characterize European populations, whereas the 11778 and 14484 mutations showed a strong preferential association with haplotype J. The findings suggested that one ancient combination of haplotype J with specific mutations increases the penetrance of the 2 primary mutations 11778 and 14484. Chinnery et al. (2001) analyzed 17 independent pedigrees that harbored the 11778G-A mutation. They made the following observations: (1) The frequency of blindness in males was related to the mutation load in the individual's blood. (2) Mothers with 80% or less mutant mtDNA in blood were less likely to have clinically affected sons than mothers with 100% mutant mtDNA in their blood. (3) Within individual lineages, changes in mutation load from one generation to the next were largely determined by random genetic drift. Wong et al. (2002) created cybrids using a neuronal precursor cell line, NT2, containing mitochondria from patient lymphoblasts bearing the most common LHON mutation, 11778, and the most severe LHON mutation, 3460 (516000.0001). The undifferentiated LHON-NT2 mutant cells were not significantly different from the parental cell control in terms of mtDNA/nDNA ratio, mitochondrial membrane potential, reactive oxygen species (ROS) production, or the ability to reduce the reagent Alamar blue. Differentiation of NT2s resulted in a neuronal morphology, a neuron-specific pattern of gene expression, and a 3-fold reduction in mtDNA/nDNA ratio in both mutant and control cells; however, the differentiation protocol yielded 30% less LHON cells than controls, indicating either a decreased proliferative potential or increased cell death of the LHON-NT2 cells. Differentiation of the cells to the neuronal form also resulted in significant increases in ROS production in the LHON-NT2 neurons versus controls, which was abolished by rotenone (a specific inhibitor of complex I). Wong et al. (2002) inferred that the LHON genotype may require a differentiated neuronal environment in order to induce increased mitochondrial ROS, which may be the cause of the reduced NT2 yield. They hypothesized that the LHON degenerative phenotype may be the result of an increase in mitochondrial superoxide which is caused by the LHON mutations, possibly mediated through neuron-specific alterations in complex I structure. Guy et al. (2002) found that cybrid cells containing the 11778G-A mutation showed a 60% reduction in the rate of complex I-dependent ATP synthesis compared to wildtype cells. Using 'allotopic expression,' a technique in which a mitochondrial gene is expressed in the nucleus and the protein product is then imported back to the mitochondria, Guy et al. (2002) transfected a fusion ND4 subunit gene into cybrids containing the 11778G-A mutation. Cybrid cell survival after 3 days was 3-fold greater for the allotopically transfected cells, and these cells showed a 3-fold increase in the rate of complex I-dependent ATP synthesis, to a level indistinguishable from that in normal cybrids. Guy et al. (2002) suggested that this rescue of a severe oxidative phosphorylation deficiency held promise for development of gene therapy for mitochondrial disorders. Mimaki et al. (2003) reported a male patient with LHON and cardiomyopathy who had the 11778G-A mutation as well as a 12192G-A mutation in the MTTH gene (590040.0001), which is a risk factor for cardiomyopathy. Because no case of LHON presenting with cardiomyopathy had previously been reported, the findings suggested that this was an instance of double pathogenic mtDNA mutations associated either synergistically or concomitantly with 2 different clinical manifestations. In a study of 87 index cases with LHON sequentially diagnosed in Italy, including an extremely large Brazilian family of Italian maternal ancestry, 67 subjects had the 11778/ND4 mutation. Carelli et al. (2006) concluded that the large majority of LHON mutations were due to independent mutational events. In the 87 index cases, only 7 pairs and 3 triplets of identical haplotypes were observed. Assignment of the mutational events into haplogroups confirmed that J1 and J2 play a role in LHON expression but narrowed the association to the subclades J1c and J2b, thus suggesting that 2 specific combinations of amino acid changes in cytochrome b (516020) are the cause of the mtDNA background effect and that this may occur at the level of the supercomplex formed by respiratory chain complexes I and III. Phasukkijwatana et al. (2006) examined 30 unrelated pedigrees of Thai or Chinese origin with LHON and the 11778G-A mutation. Compared to Caucasian and Japanese populations with the same mutation, the pedigrees in the study showed a lower male-to-female ratio (2.6:1) of affected persons and a higher prevalence of blood heteroplasmy (37% of the pedigrees contained at least 1 heteroplasmic 11778G-A individual). The estimated overall penetrance was 37% for males and 13% for females. In affected members of a 3-generation Chinese family that exhibited high penetrance and expressivity of visual impairment due to LHON, Qu et al. (2006) identified the homoplasmic 11778G-A mutation and 35 other variants in the MTND4 gene belonging to the Asian haplogroup D5. One of the other variants, a novel homoplasmic 4435A-G mutation, which is localized at the 3-prime end adjacent to the anticodon, at conventional position 37 (A37), was absent in 164 Chinese controls. A37 in MTND4 is extraordinarily conserved from bacteria to human mitochondria. The modified A37 was shown to contribute to the high fidelity of codon recognition and to the structural formation and stabilization of functional tRNAs. A significant reduction of the steady state levels in tRNA-Met was observed in cells carrying both the 4435A-G and 11778G-A mutations but not in cells carrying only the 11778G-A mutation. Thus, a failure in mitochondrial tRNA metabolism, caused by the 4435A-G mutation, might worsen the mitochondrial dysfunction associated with the primary 11778G-A mutation. Qu et al. (2006) concluded that the novel 4435A-G mutation had a potential modifier role in increasing the penetrance and expressivity of the primary LHON-associated G11778A mutation in the Chinese family. To create an animal model of LHON, Ellouze et al. (2008) introduced the human ND4 gene harboring the 11778G-A mutation, responsible for 60% of LHON cases, into rat eyes by in vivo electroporation. The treatment induced the degeneration of retinal ganglion cells, which were 40% less abundant in treated eyes than in control eyes. This deleterious effect was also confirmed in primary cell culture, in which both RGC survival and neurite outgrowth were compromised. Importantly, RGC loss was clearly associated with a decline in visual performance. A subsequent electroporation with wildtype ND4 prevented both RGC loss and the impairment of visual function. Ellouze et al. (2008) concluded that their data provided the proof of principle that optimized allotopic expression can be an effective treatment for LHON, and that they opened the way to clinical studies of other devastating mitochondrial disorders. By studying the penetrance of LHON in 1,859 individuals from 182 Chinese families (including 1 from Cambodia) with the MTND4 11778G-A mutation, Ji et al. (2008) found that mitochondrial haplogroup M7b1-prime-2 was associated with increased risk of visual loss, whereas the M8a haplogroup was associated with decreased risk of visual loss. Further sequence analysis suggested that the M7b1-prime-2 effect was due to variation in the MTND5 (516005) gene, and that the M8a effect was due to variation in the MTATP6 gene (516060). See LOAM (308905) for discussion of a form of LHON with increased penetrance and earlier age of onset resulting from additional mutation in the PRICKLE3 gene (300111.0001) acting as a modifier of disease expression. (less)

Abnormality of the skull (present) , Morphological abnormality of the central nervous system (present) , Cognitive impairment (present) , Abnormality of coordination (present) , Memory impairment (present) , Anxiety (present) , Depressivity (present) , Hyperpigmentation of the skin (present) , Hypohidrosis (present) , Generalized abnormality of skin (present) , Epidermal thickening (present) , Joint hypermobility (present) , Abnormality of digit (present) , Abnormality of muscle physiology (present) , Abnormality of the musculature of the limbs (present) , Abnormality of the liver (present) (less)