A splice donor mutation inNAA10results in the dysregulation of the retinoic acid signalling pathway and causes Lenz microphthalmia syndrome

Abstract

Introduction Lenz microphthalmia syndrome (LMS) is a genetically heterogeneous X-linked disorder characterised by microphthalmia/anophthalmia, skeletal abnormalities, genitourinary malformations, and anomalies of the digits, ears, and teeth. Intellectual disability and seizure disorders are seen in about 60% of affected males. To date, no gene has been identified for LMS in the microphthalmia syndrome 1 locus (MCOPS1). In this study, we aim to find the disease-causing gene for this condition. Methods and results Using exome sequencing in a family with three affected brothers, we identified a mutation in the intron 7 splice donor site (c.471+2T→A) of the N-acetyltransferase NAA10 gene. NAA10 has been previously shown to be mutated in patients with Ogden syndrome, which is clinically distinct from LMS. Linkage studies for this family mapped the disease locus to Xq27-Xq28, which was consistent with the locus of NAA10. The mutation co-segregated with the phenotype and cDNA analysis showed aberrant transcripts. Patient fibroblasts lacked expression of full length NAA10 protein and displayed cell proliferation defects. Expression array studies showed significant dysregulation of genes associated with genetic forms of anophthalmia such as BMP4, STRA6, and downstream targets of BCOR and the canonical WNT pathway. In particular, STRA6 is a retinol binding protein receptor that mediates cellular uptake of retinol/vitamin A and plays a major role in regulating the retinoic acid signalling pathway. A retinol uptake assay showed that retinol uptake was decreased in patient cells. Conclusions We conclude that the NAA10 mutation is the cause of LMS in this family, likely through the dysregulation of the retinoic acid signalling pathway.

NAA10 polyadenylation signal variants cause syndromic microphthalmia

“…Specifically, for NAA10 , this suggests that partial loss of protein function due to reduced mRNA levels leads to a distinct phenotype, as compared with missense variants where the functional deficiency may only affect specific acetylation or DNA binding functions. The previously reported NAA10 splice site variant7 also showed reduced mRNA/protein supporting reduced function as causal for the microphthalmia phenotype. Alternatively, sequences within the elongated 3′ end, or within the retained intron 7 for the splice variant, may have a novel functional effect.…”

“…Clinical presentation in one-third of affected individuals is syndromic,1 2 and it is genetically heterogeneous 3. X-linked syndromic anophthalmia and microphthalmia have been shown to result from pathogenic variants in four genes: BCOR 4 (MIM:300485, MCOPS2), HCCS 5 (MIM:300056, MCOPS7), HMGB3 6 (MIM:300193, MCOPS13), and NAA10 7 (MIM:309800, MCOPS1). A fifth locus, MCOPS4 (MIM:301590, also designated as ANOP1), with linkage to Xq27-q28, was specified without identification of an associated gene.…”

The world of protein acetylation

“…Another disease connected to a dysfunctional Naa10 is Lenz microphthalmia syndrome (LMS), characterized with congenital bilateral anophthalemia, postnatal growth failure, hypotonia and skeletal anomalies, mild to severe intellectual disability and delayed motor development, yet clinically distinct and with a milder phenotype than observed for the Ogden syndrome males [22]. The splice donor mutation (c.471+2TA) in intron 7 of NAA10 results in alternative splicing, aberrant NAA10 transcripts and a C-terminally truncated Naa10, but a maintained NAT catalytic domain [129]. However, the mutation results in lack of wt Naa10 protein expression in addition to low expression of aberrant Naa10 transcripts, a combination that most likely results in reduced Nt-acetylation of NatA-type proteins essential for normal development.…”

“…14 expressed in these splice donor mutated cells, in particular genes associated with the retinoic acid and Wnt signaling pathways, both necessary for normal eye development [129].…”

N-terminal acetylation promotes synaptonemal complex assembly in C. elegans

“…About 50%-70% of proteins are N-terminally acetylated in yeast, and 80%-90% of the soluble proteins are N-terminally acetylated in human cells (Arnesen et al 2009;Van Damme et al 2011). Mutations in NATs are associated with various phenotypes in different organisms, including in humans, where mutations in NAA10, the catalytic subunit of NatA, lead to a global developmental delay and Ogden and Lenz microphthalmia syndromes (Rope et al 2011;Esmailpour et al 2014;Myklebust et al 2015;Popp et al 2015). Despite its abundance, the molecular functions of this modification have been characterized for only a handful of cases, where N-terminal acetylation can affect protein targeting to membranes, protein-protein interactions, protein folding, or protein degradation (Urbancikova and Hitchcock-DeGregori 1994;Setty et al 2004;Arnesen et al 2010;Hwang et al 2010;Scott et al 2011;Holmes et al 2014).…”