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Original article
A splice donor mutation in NAA10 results in the dysregulation of the retinoic acid signalling pathway and causes Lenz microphthalmia syndrome
  1. Taraneh Esmailpour1,2,
  2. Hamidreza Riazifar1,
  3. Linan Liu1,
  4. Sandra Donkervoort1,3,
  5. Vincent H Huang1,
  6. Shreshtha Madaan1,
  7. Bassem M Shoucri1,
  8. Anke Busch4,
  9. Jie Wu5,
  10. Alexander Towbin6,
  11. Robert B Chadwick5,
  12. Adolfo Sequeira7,
  13. Marquis P Vawter7,
  14. Guoli Sun8,
  15. Jennifer J Johnston9,
  16. Leslie G Biesecker9,
  17. Riki Kawaguchi10,
  18. Hui Sun10,
  19. Virginia Kimonis1,
  20. Taosheng Huang1,2,8,11,12,13
  1. 1Department of Pediatrics, Division of Human Genetics, University of California Irvine, Irvine, California, USA
  2. 2Department of Pathology, University of California Irvine, Irvine, California, USA
  3. 3Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institutes of Health, National Institute of Neurological Disorders and Stroke, Neurogenetics Branch, Bethesda, Maryland, USA
  4. 4Department of Microbiology and Molecular Genetics, University of California Irvine, Irvine, California, USA
  5. 5UCI Genomic High-Throughput Facility, Department of Biological Chemistry, University of California Irvine, Irvine, California, USA
  6. 6Division of Radiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
  7. 7Functional Genomics Laboratory, Department of Psychiatry & Human Behavior, University of California Irvine, Irvine, California, USA
  8. 8Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
  9. 9Genetic Disease Research Branch, National Human Genome Research Institute, Bethesda, Maryland, USA
  10. 10Department of Physiology, Jules Stein Eye Institute, and Howard Hughes Medical Institute, University of California, Los Angeles, California, USA
  11. 11Department of Developmental and Cell Biology, University of California, Irvine, California, USA
  12. 12Department of Ophthalmology, University of California, Irvine, California, USA
  13. 13Department of Pathology, MitoMed Molecular Diagnostic Laboratory, University of California Irvine, Irvine, California, USA
  1. Correspondence to Dr Taosheng Huang, Division of Human Genetics, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Building R, Room 1027, MLC 7016, Cincinnati, OH 45229, USA; Taosheng.Huang{at}cchmc.org

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.

  • Clinical Genetics
  • Developmental
  • Genome-Wide
  • Lenz Microphthalmia Syndrome
  • NAA10

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