Khan, Muzammil A., Rupp, Verena M., Orpinell, Meritxell, Hussain, Muhammad S., Altmueller, Janine, Steinmetz, Michel O., Enzinger, Christian, Thiele, Holger, Hoehne, Wolfgang, Nuernberg, Gudrun, Baig, Shahid M., Ansar, Muhammad ORCID: 0000-0001-5891-7063, Nuernberg, Peter, Vincent, John B., Speicher, Michael R., Goenczy, Pierre and Windpassinger, Christian (2014). A missense mutation in the PISA domain of HsSAS-6 causes autosomal recessive primary microcephaly in a large consanguineous Pakistani family. Hum. Mol. Genet., 23 (22). S. 5940 - 5950. OXFORD: OXFORD UNIV PRESS. ISSN 1460-2083

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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 PISAdomain 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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Khan, Muzammil A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rupp, Verena M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Orpinell, MeritxellUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hussain, Muhammad S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Altmueller, JanineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Steinmetz, Michel O.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Enzinger, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thiele, HolgerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hoehne, WolfgangUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nuernberg, GudrunUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Baig, Shahid M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ansar, MuhammadUNSPECIFIEDorcid.org/0000-0001-5891-7063UNSPECIFIED
Nuernberg, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vincent, John B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Speicher, Michael R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Goenczy, PierreUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Windpassinger, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-423287
DOI: 10.1093/hmg/ddu318
Journal or Publication Title: Hum. Mol. Genet.
Volume: 23
Number: 22
Page Range: S. 5940 - 5950
Date: 2014
Publisher: OXFORD UNIV PRESS
Place of Publication: OXFORD
ISSN: 1460-2083
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
MULTIPLE SEQUENCE ALIGNMENT; HUMAN GENOME; CENTROSOME DUPLICATION; GENETIC-HETEROGENEITY; 9-FOLD SYMMETRY; HUMAN-CELLS; PROTEIN; CENTRIOLE; CYCLE; SAS-6Multiple languages
Biochemistry & Molecular Biology; Genetics & HeredityMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/42328

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