ClinVar Genomic variation as it relates to human health

In 3 children born to consanguineous Moroccan parents with a progressive mitochondrial myopathy and combined respiratory chain deficiency (MPMCD; 613076), Di Fonzo et al. (2009) identified a homozygous G-to-A transition at nucleotide 581 in exon 3 of the GFER gene, resulting in an arg-to-his substitution at codon 194 (R194H). This mutation was not identified in 380 samples from unrelated European individuals and 183 samples from unrelated Arab individuals, including 156 Moroccans. Confocal microscopy and immunoblot analysis showed that R194H mutant GFER is less stable than wildtype protein within the mitochondria. By next-generation sequencing of a nuclear gene panel for mitochondrial disease, Calderwood et al. (2016) identified a patient with MPMCD who was compound heterozygous for mutations in the GFER gene: R194H and a c.373C-T transition, resulting in a gln125-to-ter substitution (Q125X; 600294.0002). This patient also had adrenal insufficiency and had previously been reported by North et al. (1996). In 2 sibs (patients 3 and 4) with MPMCD, Nambot et al. (2017) identified compound heterozygous mutations in the GFER gene: R194H and a 1-bp deletion in exon 1 (c.217delG; 600924.0005), resulting in a frameshift and a premature stop codon (600924.0005). Each parent was heterozygous for one of the mutations. Neither variant was present in the ExAC database. Variant Function Ceh-Pavia et al. (2014) characterized recombinant yeast Erv1 containing an R182H mutation, which corresponds to the R194H mutation in the human ortholog. The mutation did not affect the FAD content of Erv1, but it disturbed the secondary, tertiary, and quaternary structures of Erv1, with the mutant protein forming a dimer instead of a tetramer like wildtype. The Erv1 R182H mutant had both decreased thermal stability and weaker FAD-binding compared with wildtype. The mutation not only caused a defect in Erv1 shuttling of electrons to molecular oxygen, but also in the ability of Erv1 to reduce cytochrome c. The gradual inactivation of Erv1 resulted from loss of cofactor during the catalytic reaction, and this functional defect could be rescued with the addition of extra FAD or excessive Erv1 in vitro. Likewise, the growth defect of the Erv1 R182H mutant yeast strain could be rescued by increasing the concentration of the mutant protein through overexpression in vivo. By structural and other analyses of human ALR, Daithankar et al. (2010) found that the R194H mutation had a large effect on protein stability and flavin binding, but that it did not impact enzyme activity and other biophysical features of ALR. (less)