Novel mutations in ALDH1A3 associated with autosomal recessive anophthalmia/microphthalmia, and review of the literature

Abstract

BackgroundAutosomal recessive anophthalmia and microphthalmia are rare developmental eye defects occurring during early fetal development. Syndromic and non-syndromic forms of anophthalmia and microphthalmia demonstrate extensive genetic and allelic heterogeneity. To date, disease mutations have been identified in 29 causative genes associated with anophthalmia and microphthalmia, with autosomal dominant, autosomal recessive and X-linked inheritance patterns described. Biallelic ALDH1A3 gene variants are the leading genetic causes of autosomal recessive anophthalmia and microphthalmia in countries with frequent parental consanguinity.MethodsThis study describes genetic investigations in two consanguineous Pakistani families with a total of seven affected individuals with bilateral non-syndromic clinical anophthalmia.ResultsUsing whole exome and Sanger sequencing, we identified two novel homozygous ALDH1A3 sequence variants as likely responsible for the condition in each family; missense mutation [NM_000693.3:c.1240G > C, p.Gly414Arg; Chr15:101447332G > C (GRCh37)] in exon 11 (family 1), and, a frameshift mutation [NM_000693.3:c.172dup, p.Glu58Glyfs*5; Chr15:101425544dup (GRCh37)] in exon 2 predicted to result in protein truncation (family 2).ConclusionsThis study expands the molecular spectrum of pathogenic ALDH1A3 variants associated with anophthalmia and microphthalmia, and provides further insight of the key role of the ALDH1A3 in human eye development.Electronic supplementary materialThe online version of this article (10.1186/s12881-018-0678-6) contains supplementary material, which is available to authorized users.

Ocular coloboma: Genetic variants reveal a dynamic model of eye development

“…Mutations in RETINOL‐BINDING PROTEIN ( RBP4 , OMIM 180250), a transport protein for retinol in serum, and in STIMULATED BY RETINOIC ACID 6 ( STRA6 , OMIM 610745), a transmembrane receptor that mediates uptake of vitamin A, have been associated anophthalmia and microphthalmia (Casey et al, 2011; Cukras et al, 2012; White et al, 2008). Furthermore, mutations in ALDEHYDE DEHYDROGENASE 1 FAMILY , MEMBER A3 ( ALDH1A3 , also known as RALDH3 , OMIM 600463) are known to cause microphthalmia, anophthalmia, and coloboma (Abouzeid et al, 2014; Lin et al, 2018; Roos et al, 2014). During eye development, RA is synthesized in the optic vesicle, the surrounding mesenchyme, and the lens placode (Cvekl & Tamm, 2004; Heavner & Pevny, 2012).…”

Genetics of anophthalmia and microphthalmia. Part 1: Non-syndromic anophthalmia/microphthalmia

“…1b. Since then, ALDH1A3 has been implicated in many reports of recessive forms of A/M(Abouzeid et al 2014;Alabdullatif et al 2017;Aldahmesh et al 2013b;Dehghani et al 2017;Lin et al 2018;Liu et al 2017b;Mory et al 2013;Roos et al 2013;Semerci et al 2014;Ullah et al 2016;Yahyavi et al 2013). Mutations in ALDH1A3 are a frequent cause of A/M in consanguineous pedigrees(Abouzeid et al 2014), representing approximately 10% of cases.…”

ALDH1A3 Segregated Expression and Nucleus-Associated Proteasomal Degradation Are Common Traits of Glioblastoma Stem Cells

“…In this regard, it is noteworthy that mutant ALDH1A3 proteins can be generated via the aberrant alternative splicing or gene fusions involving the ALDH1A3 gene. Indeed, a number of intronic mutations, leading to the ALDH1A3 aberrant splicing [35,36] as well as ALDH1A3 fusion transcripts (http://atlasgeneticsoncology.org/ Genes/GC_ALDH1A3.html accessed on 17 December 2021), have been identified. Interestingly, one of the known fusion partners of ALDH1A3 is USP25, a ubiquitin-dependent protease, which localizes in both nucleus and cytoplasm and has been implicated as a tumor-promoting factor in different types of human cancers [37].…”