Top

Published in:

Open Access 01-12-2018 | Research article

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

Authors: Siying Lin, Gaurav V. Harlalka, Abdul Hameed, Hadia Moattar Reham, Muhammad Yasin, Noor Muhammad, Saadullah Khan, Emma L. Baple, Andrew H. Crosby, Shamim Saleha

Published in: BMC Medical Genetics | Issue 1/2018

Abstract

Background

Autosomal 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.

Methods

This study describes genetic investigations in two consanguineous Pakistani families with a total of seven affected individuals with bilateral non-syndromic clinical anophthalmia.

Results

Using 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).

Conclusions

This 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.

Available only for authorised users

Verma AS, FitzPatrick DR. Anophthalmia and microphthalmia. Orphanet J Rare Dis. 2007;2:47. https://doi.org/10.1186/1750-1172-2-47.CrossRefPubMedPubMedCentral

Bardakjian TM, Schneider A. The genetics of anophthalmia and microphthalmia. Curr Opin Ophthalmol. 2011;22(5):309–13. https://doi.org/10.1097/ICU.0b013e328349b004.CrossRefPubMed

Ullah E, Nadeem Saqib MA, Sajid S, Shah N, Zubair M, Khan MA, et al. Genetic analysis of consanguineous families presenting with congenital ocular defects. Exp Eye Res. 2016;146:163–71. https://doi.org/10.1016/j.exer.2016.03.014.CrossRefPubMed

Williamson KA, FitzPatrick DR. The genetic architecture of microphthalmia, anophthalmia and coloboma. Eur J Med Genet. 2014;57(8):369–80. https://doi.org/10.1016/j.ejmg.2014.05.002.CrossRefPubMed

Yahyavi M, Abouzeid H, Gawdat G, de Preux AS, Xiao T, Bardakjian T, et al. ALDH1A3 loss of function causes bilateral anophthalmia/ microphthalmia and hypoplasia of the optic nerve and optic chiasm. Hum Mol Genet. 2013;22(16):3250–8. https://doi.org/10.1093/hmg/ddt179.CrossRefPubMedPubMedCentral

Fares-Taie L, Gerber S, Chassaing N, Clayton-Smith J, Hanein S, Silva E, et al. ALDH1A3 mutations cause recessive anophthalmia and microphthalmia. Am J Hum Genet. 2013;92(2):265–70. https://doi.org/10.1016/j.ajhg.2012.12.003.CrossRefPubMedPubMedCentral

Ragge NK, Subak-Sharpe ID, Collin JR. A practical guide to the management of anophthalmia and microphthalmia. Eye (Lond). 2007;21(10):1290–300. https://doi.org/10.1038/sj.eye.6702858.CrossRef

Jimenez NL, Flannick J, Yahyavi M, Li J, Bardakjian T, Tonkin L, et al. Targeted ‘next-generation’ sequencing in anophthalmia and microphthalmia patients confirms SOX2, OTX2 and FOXE3 mutations. BMC Med Genet. 2011;12:172. https://doi.org/10.1186/1471-2350-12-172.CrossRefPubMed

Kumar S, Sandell LL, Trainor PA, Koentgen F, Duester G. Alcohol and aldehyde dehydrogenases: retinoid metabolic effects in mouse knockout models. Biochim Biophys Acta. 2012;1821(1):198–205. https://doi.org/10.1016/j.bbalip.2011.04.004.CrossRefPubMed

10.

Xu J, Wang H, Liang T, Cai X, Rao X, Huang Z, Sheng G. Retinoic acid promotes neural conversion of mouse embryonic stem cell in adherent monoculture. Mol Biol Rep. 2012;39(2):789–95. https://doi.org/10.1007/s11033-011-0800-8.CrossRefPubMed

11.

Moretti A, Li J, Donini S, Sobol RW, Rizzi M, Garavaglia S. Crystal structure of human aldehyde dehydrogenase 1A3 complexed with NAD+ and retinoic acid. Sci Rep. 2016;6:35710. https://doi.org/10.1038/srep35710.CrossRefPubMedPubMedCentral

12.

Braun T, Bober E, Singh S, Agarwal DP, Goedde HW. Evidence for a signal peptide at the amino-terminal end of human mitochondrial aldehyde dehydrogenase. FEBS Lett. 1987;215(2):233–6.CrossRefPubMed

13.

Plaisancié J, Brémond-Gignac D, Demeer B, Gaston V, Verloes A, Fares-Taie L, et al. Incomplete penetrance of biallelic ALDH1A3 mutations. Eur J Med Genet. 2016;59(4):215–8. https://doi.org/10.1016/j.ejmg.2016.02.004.CrossRefPubMed

14.

Aldahmesh MA, Khan AO, Hijazi H, Alkuraya FS. Mutations in ALDH1A3 cause microphthalmia. Clin Genet. 2013;84(2):128–31. https://doi.org/10.1111/cge.12184.CrossRefPubMed

15.

Mory A, Ruiz FX, Dagan E, Yakovtseva EA, Kurolap A, Parés X, et al. A missense mutation in ALDH1A3 causes isolated microphthalmia/anophthalmia in nine individuals from an inbred Muslim kindred. Eur J Hum Genet. 2014;22(3):419–22. https://doi.org/10.1038/ejhg.2013.157.CrossRefPubMed

16.

Roos L, Fang M, Dali C, Jensen H, Christoffersen N, Wu B, et al. A homozygous mutation in a consanguineous family consolidates the role of ALDH1A3 in autosomal recessive microphthalmia. Clin Genet. 2014;86(3):276–81. https://doi.org/10.1111/cge.12277.CrossRefPubMed

17.

Abouzeid H, Favez T, Schmid A, Agosti C, Youssef M, Marzouk I, et al. Mutations in ALDH1A3 represent a frequent cause of microphthalmia/anophthalmia in consanguineous families. Hum Mutat. 2014;35(8):949–53. https://doi.org/10.1002/humu.22580.CrossRefPubMed

18.

Semerci CN, Kalay E, Yıldırım C, Dinçer T, Olmez A, Toraman B, et al. Novel splice-site and missense mutations in the ALDH1A3 gene underlying autosomal recessive anophthalmia/microphthalmia. Br J Ophthalmol. 2014;98(6):832–40. https://doi.org/10.1136/bjophthalmol-2013-304058.CrossRefPubMed

19.

Dehghani M, Dehghan Tezerjani M, Metanat Z, Vahidi Mehrjardi MY. A Novel Missense Mutation in the ALDH13 Gene Causes Anophthalmia in Two Unrelated Iranian Consanguineous Families. Int J Mol Cell Med. 2017;6(2):131–4. https://doi.org/10.22088/acadpub.BUMS.6.2.7.PubMedPubMedCentralCrossRef

20.

Alabdullatif MA, Al Dhaibani MA, Khassawneh MY, El-Hattab AW. Chromosomal microarray in a highly consanguineous population: diagnosticyield, utility of regions of homozygosity, and novel mutations. Clin Genet. 2017;91(4):616–22. https://doi.org/10.1111/cge.12872.

21.

Liu Y, Lu Y, Liu S, Liao S. Novel compound heterozygous mutations of ALDH1A3 contribute to anophthalmia in a non-consanguineous Chinese family. Genet Mol Biol. 2017;40(2):430–5. https://doi.org/10.1590/1678-4685-GMB-2016-0120.CrossRefPubMedPubMedCentral

22.

Bittles AH. A community genetics perspective on consanguineous marriage. Community Genet. 2008;11(6):324–30. https://doi.org/10.1159/000133304.PubMedCrossRef

23.

Brambring M, Asbrock D. Validity of false belief tasks in blind children. J Autism Dev Disord. 2010;40:1471–84. https://doi.org/10.1007/s10803-010-1002-2.CrossRefPubMed

24.

Brown R, Hobson RP, Lee A, Stevenson J. Are there “autistic-like” features in congenitally blind children? J Child Psychol Psychiatry. 1997;38:693–703.CrossRefPubMed

25.

Musante L, Ropers HH. Genetics of recessive cognitive disorders. Trends Genet. 2014;30:32–9. https://doi.org/10.1016/j.tig.2013.09.008.CrossRefPubMed

26.

Hornby SJ, Ward SJ, Gilbert CE, Dandona L, Foster A, Jones RB. Environmental risk factors in congenital malformations of the eye. Ann Trop Paediatr. 2002;22:67–77. https://doi.org/10.1179/027249302125000193.CrossRefPubMed

27.

Schittkowski MP, Guthoff RF. Systemic and ophthalmological anomalies in congenital anophthalmic or microphthalmia patients. Br J Ophthalmol. 2010;94:487–93. https://doi.org/10.1136/bjo.2009.163436.CrossRefPubMed

Title: Novel mutations in ALDH1A3 associated with autosomal recessive anophthalmia/microphthalmia, and review of the literature
Authors: Siying Lin
Gaurav V. Harlalka
Abdul Hameed
Hadia Moattar Reham
Muhammad Yasin
Noor Muhammad
Saadullah Khan
Emma L. Baple
Andrew H. Crosby
Shamim Saleha
Publication date: 01-12-2018
Publisher: BioMed Central
Published in: BMC Medical Genetics / Issue 1/2018
Electronic ISSN: 1471-2350
DOI: https://doi.org/10.1186/s12881-018-0678-6

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

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

Abstract

Background

Methods

Results

Conclusions

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2018

Molecular genetic characterization of cblC defects in 126 pedigrees and prenatal genetic diagnosis of pedigrees with combined methylmalonic aciduria and homocystinuria

FLNA mutations in surviving males presenting with connective tissue findings: two new case reports and review of the literature

Expansion of phenotypic spectrum of MYO15A pathogenic variants to include postlingual onset of progressive partial deafness

Mutational screening of inverted formin 2 in adult-onset focal segmental glomerulosclerosis or minimal change patients from the Czech Republic

Chinese cases of early infantile epileptic encephalopathy: a novel mutation in the PCDH19 gene was proved in a mosaic male- case report

Functional confirmation that the R1488* variant in SCN9A results in complete loss-of-function of Nav1.7