title: A missense mutation in the PISA domain of HsSAS-6 causes autosomal recessive primary microcephaly in a large consanguineous Pakistani family.
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.
authors.affiliation: Gomal Centre of Biochemistry and Biotechnology, Gomal University D.I.Khan, Khyber Pakhtoonkhuwa, Pakistan.
authors.forename: Muzammil A
authors.initials: MA
authors.lastname: Khan
authors.affiliation: Institute of Human Genetics and.
authors.forename: Verena M
authors.initials: VM
authors.lastname: Rupp
authors.affiliation: Swiss Institute for Experimental Cancer Research (ISREC), Swiss Federal Institute of Technology (EPFL), School of Life Sciences, Lausanne, Switzerland.
authors.forename: Meritxell
authors.initials: M
authors.lastname: Orpinell
authors.affiliation: Cologne Center for Genomics (CCG), Institute of Biochemistry I, Medical Faculty.
authors.forename: Muhammad S
authors.initials: MS
authors.lastname: Hussain
authors.affiliation: Cologne Center for Genomics (CCG), Institute of Human Genetics.
authors.forename: Janine
authors.initials: J
authors.lastname: Altmüller
authors.affiliation: Laboratory of Biomolecular Research, Department of Biology and Chemistry, Paul Scherrer Institut, Villigen PSI, Switzerland.
authors.forename: Michel O
authors.initials: MO
authors.lastname: Steinmetz
authors.affiliation: Department of Neurology, Medical University of Graz, Graz, Austria.
authors.forename: Christian
authors.initials: C
authors.lastname: Enzinger
authors.affiliation: Cologne Center for Genomics (CCG).
authors.forename: Holger
authors.initials: H
authors.lastname: Thiele
authors.affiliation: Cologne Center for Genomics (CCG).
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Höhne
authors.affiliation: Cologne Center for Genomics (CCG).
authors.forename: Gudrun
authors.initials: G
authors.lastname: Nürnberg
authors.affiliation: Human Molecular Genetics Laboratory, Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering (NIBGE), Faisalabad, Pakistan.
authors.forename: Shahid M
authors.initials: SM
authors.lastname: Baig
authors.affiliation: Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan and.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Ansar
authors.affiliation: 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.
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.affiliation: Molecular Neuropsychiatry and Development (MiND) Lab, The Campbell Family Brain Research Institute, The Centre for Addiction & Mental Health (CAMH), Toronto, Ontario, Canada.
authors.forename: John B
authors.initials: JB
authors.lastname: Vincent
authors.affiliation: Institute of Human Genetics and.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Speicher
authors.affiliation: Swiss Institute for Experimental Cancer Research (ISREC), Swiss Federal Institute of Technology (EPFL), School of Life Sciences, Lausanne, Switzerland.
authors.forename: Pierre
authors.initials: P
authors.lastname: Gönczy
authors.affiliation: Institute of Human Genetics and christian.windpassinger@medunigraz.at.
authors.forename: Christian
authors.initials: C
authors.lastname: Windpassinger
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D044466:Asian People / Q000235:genetics*; D001483:Base Sequence; D018797:Cell Cycle Proteins / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D059472:Exome; D005260:Female; D006801:Humans; D008297:Male; D008831:Microcephaly / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010154:Pakistan; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment
chemical_list: D018797:Cell Cycle Proteins; C497202:SASS6 protein, human