A novel mutation in CDK5RAP2 gene causes primary microcephaly with speech impairment and sparse eyebrows in a
Uzma Abdullah1, Muhammad Farooq2, Yuan Mang3
1Human Molecular Genetics Laboratory, National Institute for Biotechnology and Genetic Engineering (NIBGE)-PIEAS, Faisalabad, Pakistan.
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.
Insights
Mutations in the CDK5RAP2 gene cause primary microcephaly (MCPH), a developmental brain disorder. This study identifies a novel CDK5RAP2 mutation in a Pakistani family, expanding the known mutation spectrum and clinical presentation of MCPH.
Area of Science:
- Genetics
- Neuroscience
- Developmental Biology
Background:
- The CDK5RAP2 gene encodes a crucial centrosomal protein vital for fetal brain development.
- Biallelic mutations in CDK5RAP2 are a known cause of primary microcephaly (MCPH).
- The full phenotypic spectrum associated with CDK5RAP2 mutations remains incompletely understood, with limited reported cases.
Observation:
- A consanguineous Pakistani family presented with moderate to severe intellectual disability, speech impairment, short stature, and sparse eyebrows.
- Whole exome sequencing revealed a novel 2-base pair duplication in exon 34 of CDK5RAP2 in the affected individual.
- This duplication results in a frameshift mutation, premature stop codon, and a truncated protein lacking essential C-terminal domains.
Findings:
- The identified CDK5RAP2 mutation leads to a truncated protein, potentially affecting its localization to the centrosome and Golgi apparatus.
- The resultant transcript evades nonsense-mediated decay, indicating the production of a non-functional protein.
- This genetic finding provides molecular insight into the pathogenesis of microcephaly in the studied family.
Implications:
- The findings expand the known mutation spectrum for CDK5RAP2 and primary microcephaly.
- Clinical variability within the family underscores the need for comprehensive clinical characterization of patients with CDK5RAP2 mutations.
- Further research into CDK5RAP2 function and mutation effects can improve diagnosis and understanding of brain development disorders.
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