A Homozygous AKNA Frameshift Variant Is Associated with Microcephaly in a Pakistani Family
Syeda Seema Waseem1,2, Abubakar Moawia1,3,4,5, Birgit Budde1
1Cologne Center for Genomics (CCG), Faculty of Medicine, University Hospital Cologne, University of Cologne, 50931 Cologne, Germany.
Abstract:
Primary microcephaly (MCPH) is a prenatal condition of small brain size with a varying degree of intellectual disability. It is a heterogeneous genetic disorder with 28 associated genes reported so far. Most of these genes encode centrosomal proteins. Recently, AKNA was recognized as a novel centrosomal protein that regulates neurogenesis via microtubule organization, making AKNA a likely candidate gene for MCPH. Using linkage analysis and whole-exome sequencing, we found a frameshift variant in exon 12 of AKNA (NM_030767.4: c.2737delG) that cosegregates with microcephaly, mild intellectual disability and speech impairment in a consanguineous family from Pakistan. This variant is predicted to result in a protein with a truncated C-terminus (p.(Glu913Argfs*42)), which has been shown to be indispensable to AKNA's localization to the centrosome and a normal brain development. Moreover, the amino acid sequence is altered from the beginning of the second of the two PEST domains, which are rich in proline (P), glutamic acid (E), serine (S), and threonine (T) and common to rapidly degraded proteins. An impaired function of the PEST domains may affect the intracellular half-life of the protein. Our genetic findings compellingly substantiate the predicted candidacy, based on its newly ascribed functional features, of the multifaceted protein AKNA for association with MCPH.
Insights
A novel gene variant in AKNA causes primary microcephaly (MCPH), a rare brain development disorder. This genetic mutation affects protein structure, leading to impaired brain growth and intellectual disability in affected families.
Area of Science:
- Genetics
- Neuroscience
- Molecular Biology
Background:
- Primary microcephaly (MCPH) is a heterogeneous genetic disorder characterized by reduced brain size and intellectual disability.
- Most known MCPH genes encode centrosomal proteins, crucial for cell division and development.
- AKNA, a recently identified centrosomal protein, regulates neurogenesis through microtubule organization, suggesting its potential role in MCPH.
Purpose of the Study:
- To investigate the genetic basis of primary microcephaly (MCPH) in a consanguineous family.
- To identify novel genes associated with MCPH, focusing on centrosomal proteins.
- To evaluate the role of the AKNA gene in brain development and its potential link to MCPH.
Main Methods:
- Linkage analysis was employed to identify genetic markers associated with MCPH in the family.
- Whole-exome sequencing was performed to detect causative mutations within candidate genes.
- Bioinformatic tools were used to predict the functional impact of identified variants on protein structure and function.
Main Results:
- A frameshift variant (c.2737delG) in the AKNA gene was identified in affected family members.
- This variant cosegregated with the clinical phenotype of microcephaly, mild intellectual disability, and speech impairment.
- The variant is predicted to cause a truncated AKNA protein, affecting its centrosomal localization and potentially its stability due to PEST domain alteration.
Conclusions:
- The identified AKNA variant provides compelling genetic evidence for its role in primary microcephaly (MCPH).
- AKNA is implicated as a novel causative gene for MCPH, expanding the genetic landscape of this disorder.
- The findings highlight the importance of centrosomal protein function in normal brain development and underscore AKNA's multifaceted role.
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