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Novel disease loci
Original research
Single amino acid variation in MAB21L1 is dominantly associated with congenital eye defects
  1. Fanlei Meng1,2,
  2. Xin Li1,
  3. Jinlu Zhang3,
  4. Zhiyang Gao1,
  5. Xue Yang1,2,
  6. Ziqi Liu1,2,
  7. Yajie Liu1,2,
  8. Tong Guo4,
  9. Likun Wang5,
  10. Liping Yang4,
  11. Zhaohui Wang1,2
  1. 1 State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China
  2. 2 University of the Chinese Academy of Sciences, Beijing, China
  3. 3 School of Basic Medical Sciences, Peking University, Beijing, China
  4. 4 Department of Ophthalmology, Peking University Third Hospital, Beijing, China
  5. 5 Institute of Systems Biomedicine, Peking University Health Science Centre, Beijing, China
  1. Correspondence to Dr Zhaohui Wang, Beijing, China; zhwang{at}genetics.ac.cn; Dr Liping Yang; alexlipingyang{at}bjmu.edu.cn

Abstract

Background Diagnosis of a genetic disease and determination of the causative molecular lesion rely on the availability of the disease-associated pedigrees. Microphthalmia is a congenital eye defect due to an insufficiently developed visual system; its prevalence is 1–3 in 10 000 live births.

Objective We analysed a pedigree exhibiting autosomal dominant inheritance of microphthalmia to determine the genetic lesion; used AlphaFold2 to predict the changes in the protein’s 3-Dimensional structure; and compared wild-type and variant proteins in cultured cells or Drosophila model was used to explore the cellular or developmental function of the encoded product.

Results We identified a novel missense variation, F52L, in MAB21L1 that is absent in population databases and present exclusively in the individuals diagnosed with microphthalmia in this pedigree. Common structural changes were predicted for the disease-associated variants clustered at amino acids 49–52, and these variant products were also predominantly trapped in the cytoplasm of cultured human lens epithelia. To recapitulate its dominant effect in development, we expressed the Drosophila homologue corresponding to MAB21L1F52L and caused malformation of sensory organs.

Conclusion Mutations at the residues 49–52 of MAB21L1 compromise eye development. We recommend including MAB21L1 in the genetic testing panel for congenital eye disorders.

  • Genetic Counselling
  • Congenital, Hereditary, and Neonatal Diseases and Abnormalities
  • Genetic Association Studies
  • Sequence Analysis, Protein

Data availability statement

Data are available on reasonable request.

https://doi.org/10.1136/jmg-2022-108506

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    Data availability statement

    Data are available on reasonable request.

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    Footnotes

    • FM, XL and JZ contributed equally.

    • Contributors Conceptualisation: ZW, FM. Project administration: ZW, XL. Data curation: FM, XL. Formal analysis: FM, XL, JZ, ZL, ZG, XY, YL, TG, ZW. Investigation: FM, XL, ZW. Resources: LY, JZ, LW. Software: FM. Visualisation: FM, ZW. Writing—original draft: ZW. Writing—editing: ZW, FM, XL. Guarantor: ZW.

    • Funding This work is funded by National Key R&D Program of China (Grant No. 2018YFC1003300).

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.