ClinVar Genomic variation as it relates to human health

Pseudoxanthoma Elasticum In a large consanguineous Italian family segregating autosomal recessive pseudoxanthoma elasticum (PXE; 264800), Le Saux et al. (2000) identified a C-to-T transition at nucleotide 3421 in exon 24 of the ABCC6 gene, resulting in an arg-to-ter substitution at codon 1141 (R1141X). All unaffected individuals but 1 were heterozygous carriers; affected individuals were homozygous for this mutation. This variant was not found in the control panel of 200 normal alleles and cosegregated in homozygous or compound heterozygous state with the PXE phenotype in families. This mutation was also identified in 5 unrelated pedigrees. R1141X was found in homozygous state in unrelated patients with autosomal recessive PXE from the United Kingdom and Belgium. Haplotype analysis of the PXE locus in families with the R1141X mutation revealed that this mutation was segregating with different haplotypes, suggesting that R1141X may be a recurrent mutation in ABCC6. Testing of cultured skin fibroblasts showed no ABCC6 mRNA in patients carrying the R1141X mutation from the large Italian pedigree. Bergen et al. (2000) identified this mutation in 2 families segregating autosomal dominant PXE (177850). In a family in which 2 brothers and a sister had PXE, Ringpfeil et al. (2000) demonstrated that the affected individuals were compound heterozygotes for the R1141X mutation and an R1268Q mutation (603234.0011). In a cohort of 101 unrelated patients with PXE, Le Saux et al. (2001) found that the R1141X mutant allele was present in 28.4% of European alleles and only 4.1% of U.S. alleles. Also, this nonsense mutation was unequally distributed among European countries. The frequency of homozygotes was in Hardy-Weinberg equilibrium in the European population. Hu et al. (2003) demonstrated a founder effect for the R1141X mutation in the Netherlands. They identified the mutation in 19 alleles in 16 Dutch patients with PXE, in heterozygous, homozygous, or compound heterozygous form. Expression of the normal allele in heterozygotes was predominant; no or very low expression was found in homozygotes. The mutation induced instability of the aberrant mRNA. Hu et al. (2003) suggested that the PXE phenotype of the R1141X mutation most likely results from complete loss of function or functional haploinsufficiency of ABCC6. In the study of Trip et al. (2002), the presence of a single R1141X mutation in ABCC6 appeared to be an independent risk factor for coronary heart disease in young people. Generalized Arterial Calcification of Infancy 2 In 2 patients with generalized arterial calcification of infancy-2 (GACI2; 614473), Nitschke et al. (2012) identified compound heterozygosity for 2 mutations in the ABCC6 gene. A French female infant with GACI who died at 6 weeks of age, who had calcification of the coronary arteries and other arteries, severe hypertension, and heart failure, was compound heterozygous for R1141X and R1314W (603234.0006). A 3-year-old Spanish boy with GACI who had calcification of the splenic and pancreatic arteries, nephrocalcinosis, severe hypertension, cardiomegaly, psychomotor retardation, and abdominal distention, was compound heterozygous for R1141X and R518X (603234.0027). Pseudoxanthoma Elasticum, Forme Fruste, Digenic, ABCC6/GGCX In a woman and her sister with biopsy-confirmed PXE, Li et al. (2009) identified compound heterozygosity for the R1141X mutation and a mutation in the GGCX gene (V255M; 137167.0012). Neither had evidence of a coagulopathy and the skin phenotype was mild (see 177850), but skin biopsies showed undercarboxylated matrix gla proteins (MGP; 154870) in the areas of abnormal mineralization. Since R1141X in the heterozygous state is usually not associated with clinical features, the findings suggested that the women had digenic inheritance of PXE. In contrast, 2 other family members who were compound heterozygous for R1141X and another mutation in the GGCX gene (S300F; 137167.0013) had no signs of either disorder on clinical exam but refused further clinical testing. Plasma levels of undercarboxylated total MGP of the 2 clinically unaffected individuals were at the lower end of normal. Although the reasons for the lack of clinical findings in the 2 unaffected family members remained unclear, Li et al. (2009) concluded that undercarboxylation of MGP plays a critical role in aberrant mineralization of tissues in PXE. (less)

Pseudoxanthoma Elasticum In a large consanguineous Italian family segregating autosomal recessive pseudoxanthoma elasticum (PXE; 264800), Le Saux et al. (2000) identified a C-to-T transition at nucleotide 3421 in exon 24 of the ABCC6 gene, resulting in an arg-to-ter substitution at codon 1141 (R1141X). All unaffected individuals but 1 were heterozygous carriers; affected individuals were homozygous for this mutation. This variant was not found in the control panel of 200 normal alleles and cosegregated in homozygous or compound heterozygous state with the PXE phenotype in families. This mutation was also identified in 5 unrelated pedigrees. R1141X was found in homozygous state in unrelated patients with autosomal recessive PXE from the United Kingdom and Belgium. Haplotype analysis of the PXE locus in families with the R1141X mutation revealed that this mutation was segregating with different haplotypes, suggesting that R1141X may be a recurrent mutation in ABCC6. Testing of cultured skin fibroblasts showed no ABCC6 mRNA in patients carrying the R1141X mutation from the large Italian pedigree. Bergen et al. (2000) identified this mutation in 2 families segregating autosomal dominant PXE (177850). In a family in which 2 brothers and a sister had PXE, Ringpfeil et al. (2000) demonstrated that the affected individuals were compound heterozygotes for the R1141X mutation and an R1268Q mutation (603234.0011). In a cohort of 101 unrelated patients with PXE, Le Saux et al. (2001) found that the R1141X mutant allele was present in 28.4% of European alleles and only 4.1% of U.S. alleles. Also, this nonsense mutation was unequally distributed among European countries. The frequency of homozygotes was in Hardy-Weinberg equilibrium in the European population. Hu et al. (2003) demonstrated a founder effect for the R1141X mutation in the Netherlands. They identified the mutation in 19 alleles in 16 Dutch patients with PXE, in heterozygous, homozygous, or compound heterozygous form. Expression of the normal allele in heterozygotes was predominant; no or very low expression was found in homozygotes. The mutation induced instability of the aberrant mRNA. Hu et al. (2003) suggested that the PXE phenotype of the R1141X mutation most likely results from complete loss of function or functional haploinsufficiency of ABCC6. In the study of Trip et al. (2002), the presence of a single R1141X mutation in ABCC6 appeared to be an independent risk factor for coronary heart disease in young people. Generalized Arterial Calcification of Infancy 2 In 2 patients with generalized arterial calcification of infancy-2 (GACI2; 614473), Nitschke et al. (2012) identified compound heterozygosity for 2 mutations in the ABCC6 gene. A French female infant with GACI who died at 6 weeks of age, who had calcification of the coronary arteries and other arteries, severe hypertension, and heart failure, was compound heterozygous for R1141X and R1314W (603234.0006). A 3-year-old Spanish boy with GACI who had calcification of the splenic and pancreatic arteries, nephrocalcinosis, severe hypertension, cardiomegaly, psychomotor retardation, and abdominal distention, was compound heterozygous for R1141X and R518X (603234.0027). Pseudoxanthoma Elasticum, Forme Fruste, Digenic, ABCC6/GGCX In a woman and her sister with biopsy-confirmed PXE, Li et al. (2009) identified compound heterozygosity for the R1141X mutation and a mutation in the GGCX gene (V255M; 137167.0012). Neither had evidence of a coagulopathy and the skin phenotype was mild (see 177850), but skin biopsies showed undercarboxylated matrix gla proteins (MGP; 154870) in the areas of abnormal mineralization. Since R1141X in the heterozygous state is usually not associated with clinical features, the findings suggested that the women had digenic inheritance of PXE. In contrast, 2 other family members who were compound heterozygous for R1141X and another mutation in the GGCX gene (S300F; 137167.0013) had no signs of either disorder on clinical exam but refused further clinical testing. Plasma levels of undercarboxylated total MGP of the 2 clinically unaffected individuals were at the lower end of normal. Although the reasons for the lack of clinical findings in the 2 unaffected family members remained unclear, Li et al. (2009) concluded that undercarboxylation of MGP plays a critical role in aberrant mineralization of tissues in PXE. (less)