2. Academic Validation
  3. A mutation in the major autophagy gene, WIPI2, associated with global developmental abnormalities

A mutation in the major autophagy gene, WIPI2, associated with global developmental abnormalities

  • Brain. 2019 May 1;142(5):1242-1254. doi: 10.1093/brain/awz075.
Musharraf Jelani 1 2,  Hannah C Dooley 3,  Andrea Gubas 3,  Hussein Sheikh Ali Mohamoud 4,  Muhammad Tariq Masood Khan 5,  Zahir Ali 6,  Changsoo Kang 7,  Fazal Rahim 8,  Amin Jan 5,  Nirmal Vadgama 9,  Muhammad Ismail Khan 10,  Jumana Yousuf Al-Aama 1,  Asifullah Khan 11,  Sharon A Tooze 3,  Jamal Nasir 9
Affiliations

Affiliations

  • 1 Department of Genetic Medicine, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia.
  • 2 Centre for Omic Sciences, Islamia College Peshawar, Pakistan.
  • 3 The Francis Crick Institute, Molecular Cell Biology of Autophagy, London, UK.
  • 4 SW Thames Regional Genetics Laboratory, St. George's University Hospitals NHS Foundation Trust, UK.
  • 5 North West School of Medicine, Peshawar, Pakistan.
  • 6 Laboratory for Genome Engineering, Division of Biological Sciences, King Abdullah University of Science and Technology, Thuwal 23955-6900, Saudi Arabia.
  • 7 Department of Biology and Institute of Basic Sciences, Sungshin Women's University, Seoul, Republic of Korea.
  • 8 Department of Physiology, Bacha Khan Medical College, Mardan, Pakistan.
  • 9 Genetics Unit, Cell Biology and Genetics Research Centre, Molecular and Clinical Sciences Research Institute, St. George's University of London, London, UK.
  • 10 Zoology Department, Islamia College University, Peshawar, Pakistan.
  • 11 Department of Biochemistry, Abdul Wali Khan University Mardan, Pakistan.
PMID: 30968111 DOI: 10.1093/brain/awz075
Abstract

We describe a large consanguineous pedigree from a remote area of Northern Pakistan, with a complex developmental disorder associated with wide-ranging symptoms, including mental retardation, speech and language impairment and other neurological, psychiatric, skeletal and cardiac abnormalities. We initially carried out a genetic study using the HumanCytoSNP-12 v2.1 Illumina gene chip on nine family members and identified a single region of homozygosity shared amongst four affected individuals on chromosome 7p22 (positions 3059377-5478971). We performed whole-exome sequencing on two affected individuals from two separate branches of the extended pedigree and identified a novel nonsynonymous homozygous mutation in exon 9 of the WIPI2 (WD-repeat protein interacting with phosphoinositide 2) gene at position 5265458 (c.G745A;pV249M). WIPI2 plays a critical role in Autophagy, an evolutionary conserved cellular pathway implicated in a growing number of medical conditions. The mutation is situated in a highly conserved and critically important region of WIPI2, responsible for binding PI(3)P and PI(3,5)P2, an essential requirement for Autophagy to proceed. The mutation is absent in all public databases, is predicted to be damaging and segregates with the disease phenotype. We performed functional studies in vitro to determine the potential effects of the mutation on downstream pathways leading to autophagosome assembly. Binding of the V231M mutant of WIPI2b to ATG16L1 (as well as ATG5-12) is significantly reduced in GFP pull-down experiments, and fibroblasts derived from the patients show reduced WIPI2 puncta, reduced LC3 lipidation and reduced autophagic flux.

Keywords

LC3; WIPI2; autophagy; exome sequencing; gene.

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