2. Academic Validation
  3. Bi-allelic Variants in METTL5 Cause Autosomal-Recessive Intellectual Disability and Microcephaly

Bi-allelic Variants in METTL5 Cause Autosomal-Recessive Intellectual Disability and Microcephaly

  • Am J Hum Genet. 2019 Oct 3;105(4):869-878. doi: 10.1016/j.ajhg.2019.09.007.
Elodie M Richard 1,  Daniel L Polla 2,  Muhammad Zaman Assir 3,  Minerva Contreras 4,  Mohsin Shahzad 5,  Asma A Khan 6,  Attia Razzaq 7,  Javed Akram 8,  Moazzam N Tarar 9,  Thomas A Blanpied 4,  Zubair M Ahmed 1,  Rami Abou Jamra 10,  Dagmar Wieczorek 11,  Hans van Bokhoven 12,  Sheikh Riazuddin 13,  Saima Riazuddin 14
Affiliations

Affiliations

  • 1 Department of Otorhinolaryngology Head & Neck Surgery, School of Medicine, University of Maryland, Baltimore, MD 21201, USA.
  • 2 Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud university medical center, 6500 HE Nijmegen, the Netherlands; CAPES Foundation, Ministry of Education of Brazil, Brasília DF70040-020, Brazil.
  • 3 Center for Genetic Diseases, Shaheed Zulfiqar Ali Bhutto Medical University, Pakistan Institute of Medical Sciences, Islamabad 44000, Pakistan; Allama Iqbal Medical College, University of Health Sciences, Lahore 54550, Pakistan; Jinnah Burn and Reconstructive Surgery Center, Allama Iqbal Medical College, University of Health Sciences, Lahore 54550, Pakistan.
  • 4 Department of Physiology, School of Medicine, University of Maryland, Baltimore, MD 21201, USA.
  • 5 Center for Genetic Diseases, Shaheed Zulfiqar Ali Bhutto Medical University, Pakistan Institute of Medical Sciences, Islamabad 44000, Pakistan; Jinnah Burn and Reconstructive Surgery Center, Allama Iqbal Medical College, University of Health Sciences, Lahore 54550, Pakistan.
  • 6 National Centre of Excellence in Molecular Biology, University of The Punjab, Lahore 53700, Pakistan.
  • 7 Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud university medical center, 6500 HE Nijmegen, the Netherlands; National Centre of Excellence in Molecular Biology, University of The Punjab, Lahore 53700, Pakistan.
  • 8 Center for Genetic Diseases, Shaheed Zulfiqar Ali Bhutto Medical University, Pakistan Institute of Medical Sciences, Islamabad 44000, Pakistan; Jinnah Burn and Reconstructive Surgery Center, Allama Iqbal Medical College, University of Health Sciences, Lahore 54550, Pakistan; University of Health Sciences, Lahore 54000, Pakistan.
  • 9 Jinnah Burn and Reconstructive Surgery Center, Allama Iqbal Medical College, University of Health Sciences, Lahore 54550, Pakistan.
  • 10 Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany; Institute of Human Genetics, University Medical Center Leipzig, 04103 Leipzig, Germany.
  • 11 Institut für Humangenetik, Universitätsklinikum Düsseldorf, Heinrich-Heine-Universität, 40225 Düsseldorf, Germany; Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, 45147 Essen, Germany.
  • 12 Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud university medical center, 6500 HE Nijmegen, the Netherlands.
  • 13 Center for Genetic Diseases, Shaheed Zulfiqar Ali Bhutto Medical University, Pakistan Institute of Medical Sciences, Islamabad 44000, Pakistan; Jinnah Burn and Reconstructive Surgery Center, Allama Iqbal Medical College, University of Health Sciences, Lahore 54550, Pakistan; National Centre of Excellence in Molecular Biology, University of The Punjab, Lahore 53700, Pakistan. Electronic address: [email protected].
  • 14 Department of Otorhinolaryngology Head & Neck Surgery, School of Medicine, University of Maryland, Baltimore, MD 21201, USA. Electronic address: [email protected].
PMID: 31564433 DOI: 10.1016/j.ajhg.2019.09.007
Abstract

Intellectual disability (ID) is a genetically and clinically heterogeneous disorder, characterized by limited cognitive abilities and impaired adaptive behaviors. In recent years, exome sequencing (ES) has been instrumental in deciphering the genetic etiology of ID. Here, through ES of a large cohort of individuals with ID, we identified two bi-allelic frameshift variants in METTL5, c.344_345delGA (p.Arg115Asnfs∗19) and c.571_572delAA (p.Lys191Valfs∗10), in families of Pakistani and Yemenite origin. Both of these variants were segregating with moderate to severe ID, microcephaly, and various facial dysmorphisms, in an autosomal-recessive fashion. METTL5 is a member of the methyltransferase-like protein family, which encompasses proteins with a seven-beta-strand methyltransferase domain. We found METTL5 expression in various substructures of rodent and human brains and METTL5 protein to be enriched in the nucleus and synapses of the hippocampal neurons. Functional studies of these truncating variants in transiently transfected orthologous cells and cultured hippocampal rat neurons revealed no effect on the localization of METTL5 but alter its level of expression. Our in silico analysis and 3D modeling simulation predict disruption of METTL5 function by both variants. Finally, mettl5 knockdown in zebrafish resulted in microcephaly, recapitulating the human phenotype. This study provides evidence that biallelic variants in METTL5 cause ID and microcephaly in humans and highlights the essential role of METTL5 in brain development and neuronal function.

Keywords

METTL5; autosomal recessive intellectual disability; facial dysmorphism; intellectual disability; m6A methyltransferase; microcephaly; zebrafish.

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