A novel mutation in CDK5RAP2 gene causes primary microcephaly with speech impairment and sparse eyebrows in a consanguineous Pakistani family
CDK5RAP2 gene encodes a centrosomal protein, highly expressed in fetal brain and essentially indispensable for its normal development, as biallelic mutations in it lead to primary microcephaly (MCPH). Despite being known as MCPH linked gene for more than a decade, the phenotypic spectrum of CDK5RAP2...
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Published in | European journal of medical genetics Vol. 60; no. 12; pp. 627 - 630 |
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Main Authors | , , , , , , , , , , |
Format | Journal Article |
Language | English |
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Elsevier Masson SAS
01.12.2017
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Abstract | CDK5RAP2 gene encodes a centrosomal protein, highly expressed in fetal brain and essentially indispensable for its normal development, as biallelic mutations in it lead to primary microcephaly (MCPH). Despite being known as MCPH linked gene for more than a decade, the phenotypic spectrum of CDK5RAP2 mutations is still under explored as only eleven families have been reported worldwide. Here, we analyzed a consanguineous Pakistani MCPH family, characterized by moderate to severe intellectual disability, speech impairment, moderately short stature and sparse eyebrows. Whole exome sequencing of the proband identified a 2bp duplication in exon 34 of CDK5RAP2 that causes frame-shift, leading to a premature stop codon. The resultant transcript is resistant to nonsense mediated decay, suggesting that the mutation leads to a truncated protein lacking C-terminal domains; CDK5R1, and Cnn motif 2 (CM2), required for its localization to centrosome and Golgi Apparatus. Clinical variability observed in the family highlights the importance of further detailed clinical description of patients with CDK5RAP2 mutations. |
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AbstractList | CDK5RAP2 gene encodes a centrosomal protein, highly expressed in fetal brain and essentially indispensable for its normal development, as biallelic mutations in it lead to primary microcephaly (MCPH). Despite being known as MCPH linked gene for more than a decade, the phenotypic spectrum of CDK5RAP2 mutations is still under explored as only eleven families have been reported worldwide. Here, we analyzed a consanguineous Pakistani MCPH family, characterized by moderate to severe intellectual disability, speech impairment, moderately short stature and sparse eyebrows. Whole exome sequencing of the proband identified a 2bp duplication in exon 34 of CDK5RAP2 that causes frame-shift, leading to a premature stop codon. The resultant transcript is resistant to nonsense mediated decay, suggesting that the mutation leads to a truncated protein lacking C-terminal domains; CDK5R1, and Cnn motif 2 (CM2), required for its localization to centrosome and Golgi Apparatus. Clinical variability observed in the family highlights the importance of further detailed clinical description of patients with CDK5RAP2 mutations. |
Author | Mang, Yuan Faryal, Sanam Tommerup, Niels Farooq, Muhammad Marriam Bakhtiar, Syeda Fatima, Ambrin Mahmood Baig, Shahid Hansen, Lars Larsen, Lars Allan Kjaer, Klaus Wilbrandt Abdullah, Uzma |
Author_xml | – sequence: 1 givenname: Uzma surname: Abdullah fullname: Abdullah, Uzma organization: Human Molecular Genetics Laboratory, National Institute for Biotechnology and Genetic Engineering (NIBGE)-PIEAS, Faisalabad, Pakistan – sequence: 2 givenname: Muhammad surname: Farooq fullname: Farooq, Muhammad email: farooq_nibge@yahoo.com organization: Department of Cellular and Molecular Medicine, Wilhelm Johannsen Centre for Functional Genome Research, University of Copenhagen, Copenhagen, Denmark – sequence: 3 givenname: Yuan surname: Mang fullname: Mang, Yuan organization: Department of Cellular and Molecular Medicine, Wilhelm Johannsen Centre for Functional Genome Research, University of Copenhagen, Copenhagen, Denmark – sequence: 4 givenname: Syeda surname: Marriam Bakhtiar fullname: Marriam Bakhtiar, Syeda organization: Human Molecular Genetics Laboratory, National Institute for Biotechnology and Genetic Engineering (NIBGE)-PIEAS, Faisalabad, Pakistan – sequence: 5 givenname: Ambrin surname: Fatima fullname: Fatima, Ambrin organization: Human Molecular Genetics Laboratory, National Institute for Biotechnology and Genetic Engineering (NIBGE)-PIEAS, Faisalabad, Pakistan – sequence: 6 givenname: Lars surname: Hansen fullname: Hansen, Lars organization: Department of Cellular and Molecular Medicine, Wilhelm Johannsen Centre for Functional Genome Research, University of Copenhagen, Copenhagen, Denmark – sequence: 7 givenname: Klaus Wilbrandt surname: Kjaer fullname: Kjaer, Klaus Wilbrandt organization: Department of Cellular and Molecular Medicine, Wilhelm Johannsen Centre for Functional Genome Research, University of Copenhagen, Copenhagen, Denmark – sequence: 8 givenname: Lars Allan orcidid: 0000-0002-7536-1172 surname: Larsen fullname: Larsen, Lars Allan organization: Department of Cellular and Molecular Medicine, Wilhelm Johannsen Centre for Functional Genome Research, University of Copenhagen, Copenhagen, Denmark – sequence: 9 givenname: Sanam surname: Faryal fullname: Faryal, Sanam organization: Human Molecular Genetics Laboratory, National Institute for Biotechnology and Genetic Engineering (NIBGE)-PIEAS, Faisalabad, Pakistan – sequence: 10 givenname: Niels orcidid: 0000-0003-2304-0112 surname: Tommerup fullname: Tommerup, Niels organization: Department of Cellular and Molecular Medicine, Wilhelm Johannsen Centre for Functional Genome Research, University of Copenhagen, Copenhagen, Denmark – sequence: 11 givenname: Shahid surname: Mahmood Baig fullname: Mahmood Baig, Shahid email: shahid_baig2002@yahoo.com organization: Human Molecular Genetics Laboratory, National Institute for Biotechnology and Genetic Engineering (NIBGE)-PIEAS, Faisalabad, Pakistan |
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Keywords | Exome Speech impairment Pakistani Microcephaly CDK5RAP2 |
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SubjectTerms | Adult CDK5RAP2 Child Codon, Terminator - genetics Consanguinity Exome Eyebrows - abnormalities Female Frameshift Mutation Humans Intellectual Disability - diagnosis Intellectual Disability - genetics Intracellular Signaling Peptides and Proteins - genetics Intracellular Signaling Peptides and Proteins - metabolism Male Microcephaly Microcephaly - diagnosis Microcephaly - genetics Nerve Tissue Proteins - genetics Nerve Tissue Proteins - metabolism Nonsense Mediated mRNA Decay Pakistani Pedigree Speech Disorders - diagnosis Speech Disorders - genetics Speech impairment Syndrome |
Title | A novel mutation in CDK5RAP2 gene causes primary microcephaly with speech impairment and sparse eyebrows in a consanguineous Pakistani family |
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