A homozygous mutation in a consanguineous family consolidates the role of ALDH1A3 in autosomal recessive microphthalmia

Anomalies of eye development can lead to the rare eye malformations microphthalmia and anophthalmia (small or absent ocular globes), which are genetically very heterogeneous. Several genes have been associated with microphthalmia and anophthalmia, and exome sequencing has contributed to the identifi...

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Published inClinical genetics Vol. 86; no. 3; pp. 276 - 281
Main Authors Roos, L., Fang, M., Dali, C., Jensen, H., Christoffersen, N., Wu, B., Zhang, J., Xu, R., Harris, P., Xu, X., Grønskov, K., Tümer, Z.
Format Journal Article
LanguageEnglish
Published Oxford, UK Blackwell Publishing Ltd 01.09.2014
Subjects
Aldehyde Oxidoreductases - chemistry
Aldehyde Oxidoreductases - genetics
ALDH1A3
Amino Acid Sequence
Base Sequence
Consanguinity
Exome - genetics
exome sequencing
Eye diseases
Genes, Recessive - genetics
Genetic disorders
Homozygote
Humans
Microarray Analysis
microphtalmia
Microphthalmos - genetics
Microphthalmos - pathology
Models, Molecular
Molecular Sequence Data
Mutation
Pedigree
retinoic acid
Sequence Analysis, DNA
Sequence Homology
ALDH1A3
exome sequencing
retinoic acid
microphtalmia
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Summary:Anomalies of eye development can lead to the rare eye malformations microphthalmia and anophthalmia (small or absent ocular globes), which are genetically very heterogeneous. Several genes have been associated with microphthalmia and anophthalmia, and exome sequencing has contributed to the identification of new genes. Very recently, homozygous variations within ALDH1A3 have been associated with autosomal recessive microphthalmia with or without cysts or coloboma, and with variable subphenotypes of developmental delay/autism spectrum disorder in eight families. In a consanguineous family where three of the five siblings were affected with microphthalmia/coloboma, we identified a novel homozygous missense mutation in ALDH1A3 using exome sequencing. Of the three affected siblings, one had intellectual disability and one had intellectual disability and autism, while the last one presented with normal development. This study contributes further to the description of the clinical spectrum associated with ALDH1A3 mutations, and illustrates the interfamilial clinical variation observed in individuals with ALDH1A3 mutations.
Bibliography:ark:/67375/WNG-GSTMZ7ZB-5
Shenzhen Municipal Government of China - No. GJHZ20130417140916986
istex:E011863E63A1608195054FEB49869C9D9D4381C3
Fig. S1. Model of the three-dimensional structure of the ALDH1A3 protein. (a) The tertiary structure of the tetrameric sheep liver class 1 aldehyde dehydrogenase (pdb entry: 1BXS). Each of the four subunits is shown in varying grey colors. The oligomerization domains, each of which is a three stranded antiparallel β-sheet consisting of β-strings 5, 6 and 19, are shown in varying red colors. The Cys174 (shown in green) is located just at the foot of the oligomerization domain. The change of cystein to tyrosine will cause the more bulky side chain of tyrosine to clash with the Ile171 (shown in blue) which is in the C-terminal end of the central β-string 6. (b) A close-up view of the region around the Cys174 residue showing the native enzyme, where there is plenty of room for the Cys174 residue. An arrow is pointing towards the oligomerization domain with β-string 6 in the centre. (c) The Cys174Tyr enzyme, where the clash between Tyr174 and Ile171 is seen (red circle). Ile171 is seen to be located just at the end of the β-string 6, which is in the centre of the oligomerization domain. To avoid this clash the conformation of β-string 6 is likely to change and this will have an effect on the overall structure of the oligomerization domain.Fig. S2. (a) Dark adapted and light adapted electroretinography (ERG) of individual IV:1, showing undetectable rod responses and cone responses below normal. (b) Fundoscopy of individual IV:1, showing 'bone spicule' formation and arteriolar narrowing compatible with retinitis pigmentosa.
ArticleID:CGE12277
ObjectType-Case Study-2
SourceType-Scholarly Journals-1
ObjectType-Feature-4
content type line 23
ObjectType-Report-1
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ISSN:0009-9163
1399-0004
DOI:10.1111/cge.12277