NMNAT1 mutations cause Leber congenital amaurosis

Abstract

Leber congenital amaurosis (LCA) is an infantile-onset form of inherited retinal degeneration characterized by severe vision loss1, 2. Two-thirds of LCA cases are caused by mutations in 17 known disease genes3 (RetNet Retinal Information Network). Using exome sequencing, we identified a homozygous missense mutation (c.25G>A, p.Val9Met) in NMNAT1 as likely disease-causing in two siblings of a consanguineous Pakistani kindred affected by LCA. This mutation segregated with disease in their kindred, including in three other children with LCA. NMNAT1 resides in the previously identified LCA9 locus and encodes the nuclear isoform of nicotinamide mononucleotide adenylyltransferase, a rate-limiting enzyme in nicotinamide adenine dinucleotide (NAD+) biosynthesis4, 5. Functional studies showed the p.Val9Met mutation decreased NMNAT1 enzyme activity. Sequencing NMNAT1 in 284 unrelated LCA families identified 14 rare mutations in 13 additional affected individuals. These results are the first to link an NMNAT isoform to disease and indicate that NMNAT1 mutations cause LCA.

A novelHSD17B10mutation impairing the activities of the mitochondrial RNase P complex causes X-linked intractable epilepsy and neurodevelopmental regression

“…Given the apparent rare nature of the maternal half-uncles' disorder, we only examined rare variants in the proband with allele frequencies below 0.5 percent in the general population based on the 1000 Genomes Project and the UK10K Project, and with occurrence less than 10 times in 1,334 internal control exomes that we had analyzed. [21][22][23][24] After applying these data filters, only one non-synonymous hemizygous variant was found on the X chromosome in the proband. This X-linked variant was located within the gene HSD17B10 (X:g.53458504T>C), resulting in a p.K212E amino acid change.…”

“…Variants were detected, annotated, and analyzed as described. [21][22][23][24] A total of 18,466 coding variants were identified in the proband across the genome, including 18,131 single nucleotide variants and 335 indels. Because the proband's 2 maternal half-uncles died of a similar-spectrum disorder, analysis was focused on X-linked genes.…”

“…1C), which form 2 helices (residues 204-208 and residues 211-217) separated by a sharp turn. 32 K212 is in the second helix acting as the "lid" to close the active-site [17][18][19][20][21][22][23], the insertion segments for subunit-subunit interaction (residues 100-110 and residues 141-146), the catalytic triad for the dehydrogenase (S155, Y168, and K172), and the substrate-specificity loop (residues 203-220) 32 . (B) The position of p.K212E in the tetramer structure of human SDR5C1.…”

Identity-by-descent–guided mutation analysis and exome sequencing in consanguineous families reveals unusual clinical and molecular findings in retinal dystrophy

“…One of these was a known heterozygous missense mutation in NMNAT1, c.205A>G (p.Met69Val). 24 Subsequently, we evaluated NMNAT1 variants in more detail and identified a second heterozygous missense mutation, c.769G>A (p.Glu257Lys), which is a known mutation not predicted to affect protein function (see Supplementary Table S1 online). 24 In F15 (EORD), we identified a heterozygous known frameshift mutation in EYS (c.9368dup, p.Asn3123Lysfs*3).…”

“…24 Subsequently, we evaluated NMNAT1 variants in more detail and identified a second heterozygous missense mutation, c.769G>A (p.Glu257Lys), which is a known mutation not predicted to affect protein function (see Supplementary Table S1 online). 24 In F15 (EORD), we identified a heterozygous known frameshift mutation in EYS (c.9368dup, p.Asn3123Lysfs*3). 25 Subsequent Sanger sequencing of exons with a coverage below 20× did not identify a second mutation.…”