2. Academic Validation
  3. A missense mutation in the PISA domain of HsSAS-6 causes autosomal recessive primary microcephaly in a large consanguineous Pakistani family

A missense mutation in the PISA domain of HsSAS-6 causes autosomal recessive primary microcephaly in a large consanguineous Pakistani family

  • Hum Mol Genet. 2014 Nov 15;23(22):5940-9. doi: 10.1093/hmg/ddu318.
Muzammil A Khan 1,  Verena M Rupp 2,  Meritxell Orpinell 3,  Muhammad S Hussain 4,  Janine Altmüller 5,  Michel O Steinmetz 6,  Christian Enzinger 7,  Holger Thiele 8,  Wolfgang Höhne 8,  Gudrun Nürnberg 8,  Shahid M Baig 9,  Muhammad Ansar 10,  Peter Nürnberg 11,  John B Vincent 12,  Michael R Speicher 2,  Pierre Gönczy 3,  Christian Windpassinger 13
Affiliations

Affiliations

  • 1 Gomal Centre of Biochemistry and Biotechnology, Gomal University D.I.Khan, Khyber Pakhtoonkhuwa, Pakistan.
  • 2 Institute of Human Genetics and.
  • 3 Swiss Institute for Experimental Cancer Research (ISREC), Swiss Federal Institute of Technology (EPFL), School of Life Sciences, Lausanne, Switzerland.
  • 4 Cologne Center for Genomics (CCG), Institute of Biochemistry I, Medical Faculty.
  • 5 Cologne Center for Genomics (CCG), Institute of Human Genetics.
  • 6 Laboratory of Biomolecular Research, Department of Biology and Chemistry, Paul Scherrer Institut, Villigen PSI, Switzerland.
  • 7 Department of Neurology, Medical University of Graz, Graz, Austria.
  • 8 Cologne Center for Genomics (CCG).
  • 9 Human Molecular Genetics Laboratory, Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering (NIBGE), Faisalabad, Pakistan.
  • 10 Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan and.
  • 11 Cologne Center for Genomics (CCG), Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and, Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
  • 12 Molecular Neuropsychiatry and Development (MiND) Lab, The Campbell Family Brain Research Institute, The Centre for Addiction & Mental Health (CAMH), Toronto, Ontario, Canada.
  • 13 Institute of Human Genetics and christian.windpassinger@medunigraz.at.
PMID: 24951542 DOI: 10.1093/hmg/ddu318
Abstract

Asymmetric cell division is essential for normal human brain development. Mutations in several genes encoding centrosomal proteins that participate in accurate cell division have been reported to cause autosomal recessive primary microcephaly (MCPH). By homozygosity mapping including three affected individuals from a consanguineous MCPH family from Pakistan, we delineated a critical region of 18.53 Mb on Chromosome 1p21.3-1p13.1. This region contains the gene encoding HsSAS-6, a centrosomal protein primordial for seeding the formation of new centrioles during the cell cycle. Both next-generation and Sanger Sequencing revealed a homozygous c.185T>C missense mutation in the HsSAS-6 gene, resulting in a p.Ile62Thr substitution within a highly conserved region of the PISA domain of HsSAS-6. This variant is neither present in any single-nucleotide polymorphism or exome Sequencing databases nor in a Pakistani control cohort. Experiments in tissue culture cells revealed that the Ile62Thr mutant of HsSAS-6 is substantially less efficient than the wild-type protein in sustaining centriole formation. Together, our findings demonstrate a dramatic impact of the mutation p.Ile62Thr on HsSAS-6 function and add this component to the list of genes mutated in primary microcephaly.

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