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

Khan, Muzammil A. ; Rupp, Verena M. ; Orpinell, Meritxell ; Hussain, Muhammad S. ; Altmüller, Janine ; Steinmetz, Michel O. ; Enzinger, Christian ; Thiele, Holger ; Höhne, Wolfgang ; Nürnberg, Gudrun ; Baig, Shahid M. ; Ansar, Muhammad ; Nürnberg, Peter ; Vincent, John B. ; Speicher, Michael R. ; Gönczy, Pierre ; Windpassinger, Christian

In: Human Molecular Genetics, 2014, vol. 23, no. 22, p. 5940-5949

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    Titre
    • A missense mutation in the PISA domain of HsSAS-6 causes autosomal recessive primary microcephaly in a large consanguineous Pakistani family
    Auteur
    • Khan, Muzammil A.. Gomal Centre of Biochemistry and Biotechnology, Gomal University D.I.Khan, Khyber Pakhtoonkhuwa, Pakistan
    • Rupp, Verena M.. Institute of Human Genetics and
    • Orpinell, Meritxell. Swiss Institute for Experimental Cancer Research (ISREC), Swiss Federal Institute of Technology (EPFL), School of Life Sciences, Lausanne, Switzerland
    • Hussain, Muhammad S.. Cologne Center for Genomics (CCG)
    • Altmüller, Janine. Cologne Center for Genomics (CCG)
    • Steinmetz, Michel O.. Laboratory of Biomolecular Research, Department of Biology and Chemistry, Paul Scherrer Institut, Villigen PSI, Switzerland
    • Enzinger, Christian. Department of Neurology, Medical University of Graz, Graz, Austria
    • Thiele, Holger. Cologne Center for Genomics (CCG)
    • Höhne, Wolfgang. Cologne Center for Genomics (CCG)
    • Nürnberg, Gudrun. Cologne Center for Genomics (CCG)
    • Baig, Shahid M.. Human Molecular Genetics Laboratory, Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering (NIBGE), Faisalabad, Pakistan
    • Ansar, Muhammad. Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan and
    • Nürnberg, Peter. Cologne Center for Genomics (CCG)
    • Vincent, John B.. Molecular Neuropsychiatry and Development (MiND) Lab, The Campbell Family Brain Research Institute, The Centre for Addiction & Mental Health (CAMH), Toronto, Ontario, Canada
    • Speicher, Michael R.. Institute of Human Genetics and
    • Gönczy, Pierre. Swiss Institute for Experimental Cancer Research (ISREC), Swiss Federal Institute of Technology (EPFL), School of Life Sciences, Lausanne, Switzerland
    • Windpassinger, Christian. Institute of Human Genetics and
    Type de document
    • Postprint
    Langue
    • Anglais
    Publié dans
    • Human Molecular Genetics, 2014, vol. 23, no. 22, p. 5940-5949. Oxford University Press
    Autre version électronique
    Classification
    • Santé
    Identifiant OAI-PMH
    • oai:doc.rero.ch:300354
    Summary
    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