A Truncating Mutation of CEP135  Causes Primary Microcephaly and Disturbed Centrosomal Function

Muhammad Sajid Hussain, Shahid Mahmood Baig, Sascha Neumann, Gudrun Nürnberg, Muhammad Farooq, Ilyas Ahmad, Thomas Alef, Hans Christian Hennies, Martin Technau, Janine Altmüller, Peter Frommolt, Holger Thiele, Angelika Anna Noegel, Peter Nürnberg

Research output: Contribution to journalArticle

101 Citations (Scopus)

Abstract

Autosomal-recessive primary microcephaly (MCPH) is a rare congenital disorder characterized by intellectual disability, reduced brain and head size, but usually without defects in cerebral cortical architecture, and other syndromic abnormalities. MCPH is heterogeneous. The underlying genes of the seven known loci code for centrosomal proteins. We studied a family from northern Pakistan with two microcephalic children using homozygosity mapping and found suggestive linkage for regions on chromosomes 2, 4, and 9. We sequenced two positional candidate genes and identified a homozygous frameshift mutation in the gene encoding the 135 kDa centrosomal protein (CEP135), located in the linkage interval on chromosome 4, in both affected children. Post hoc whole-exome sequencing corroborated this mutation's identification as the causal variant. Fibroblasts obtained from one of the patients showed multiple and fragmented centrosomes, disorganized microtubules, and reduced growth rate. Similar effects were reported after knockdown of CEP135 through RNA interference; we could provoke them also by ectopic overexpression of the mutant protein. Our findings suggest an additional locus for MCPH at HSA 4q12 (MCPH8), further strengthen the role of centrosomes in the development of MCPH, and place CEP135 among the essential components of this important organelle in particular for a normal neurogenesis.

LanguageEnglish
Pages871-878
Number of pages8
JournalAmerican Journal of Human Genetics
Volume90
Issue number5
Early online date19 Apr 2012
DOIs
Publication statusPublished - 4 May 2012
Externally publishedYes

Fingerprint

Microcephaly
Centrosome
Chromosomes, Human, Pair 4
Mutation
Genes
Exome
Congenital, Hereditary, and Neonatal Diseases and Abnormalities
Chromosomes, Human, Pair 9
Frameshift Mutation
Chromosomes, Human, Pair 2
Pakistan
Neurogenesis
Mutant Proteins
RNA Interference
Microtubules
Intellectual Disability
Organelles
Proteins
Fibroblasts
Head

Cite this

Hussain, M. S., Baig, S. M., Neumann, S., Nürnberg, G., Farooq, M., Ahmad, I., ... Nürnberg, P. (2012). A Truncating Mutation of CEP135  Causes Primary Microcephaly and Disturbed Centrosomal Function. American Journal of Human Genetics, 90(5), 871-878. https://doi.org/10.1016/j.ajhg.2012.03.016
Hussain, Muhammad Sajid ; Baig, Shahid Mahmood ; Neumann, Sascha ; Nürnberg, Gudrun ; Farooq, Muhammad ; Ahmad, Ilyas ; Alef, Thomas ; Hennies, Hans Christian ; Technau, Martin ; Altmüller, Janine ; Frommolt, Peter ; Thiele, Holger ; Noegel, Angelika Anna ; Nürnberg, Peter. / A Truncating Mutation of CEP135  Causes Primary Microcephaly and Disturbed Centrosomal Function. In: American Journal of Human Genetics. 2012 ; Vol. 90, No. 5. pp. 871-878.
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abstract = "Autosomal-recessive primary microcephaly (MCPH) is a rare congenital disorder characterized by intellectual disability, reduced brain and head size, but usually without defects in cerebral cortical architecture, and other syndromic abnormalities. MCPH is heterogeneous. The underlying genes of the seven known loci code for centrosomal proteins. We studied a family from northern Pakistan with two microcephalic children using homozygosity mapping and found suggestive linkage for regions on chromosomes 2, 4, and 9. We sequenced two positional candidate genes and identified a homozygous frameshift mutation in the gene encoding the 135 kDa centrosomal protein (CEP135), located in the linkage interval on chromosome 4, in both affected children. Post hoc whole-exome sequencing corroborated this mutation's identification as the causal variant. Fibroblasts obtained from one of the patients showed multiple and fragmented centrosomes, disorganized microtubules, and reduced growth rate. Similar effects were reported after knockdown of CEP135 through RNA interference; we could provoke them also by ectopic overexpression of the mutant protein. Our findings suggest an additional locus for MCPH at HSA 4q12 (MCPH8), further strengthen the role of centrosomes in the development of MCPH, and place CEP135 among the essential components of this important organelle in particular for a normal neurogenesis.",
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Hussain, MS, Baig, SM, Neumann, S, Nürnberg, G, Farooq, M, Ahmad, I, Alef, T, Hennies, HC, Technau, M, Altmüller, J, Frommolt, P, Thiele, H, Noegel, AA & Nürnberg, P 2012, 'A Truncating Mutation of CEP135  Causes Primary Microcephaly and Disturbed Centrosomal Function', American Journal of Human Genetics, vol. 90, no. 5, pp. 871-878. https://doi.org/10.1016/j.ajhg.2012.03.016

A Truncating Mutation of CEP135  Causes Primary Microcephaly and Disturbed Centrosomal Function. / Hussain, Muhammad Sajid; Baig, Shahid Mahmood; Neumann, Sascha; Nürnberg, Gudrun; Farooq, Muhammad; Ahmad, Ilyas; Alef, Thomas; Hennies, Hans Christian; Technau, Martin; Altmüller, Janine; Frommolt, Peter; Thiele, Holger; Noegel, Angelika Anna; Nürnberg, Peter.

In: American Journal of Human Genetics, Vol. 90, No. 5, 04.05.2012, p. 871-878.

Research output: Contribution to journalArticle

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AU - Baig, Shahid Mahmood

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AU - Nürnberg, Gudrun

AU - Farooq, Muhammad

AU - Ahmad, Ilyas

AU - Alef, Thomas

AU - Hennies, Hans Christian

AU - Technau, Martin

AU - Altmüller, Janine

AU - Frommolt, Peter

AU - Thiele, Holger

AU - Noegel, Angelika Anna

AU - Nürnberg, Peter

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KW - Pakistan

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KW - RNA Interference

KW - Sequence Analysis, DNA

KW - Journal Article

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M3 - Article

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