A Homozygous AKNA Frameshift Variant Is Associated with Microcephaly in a Pakistani Family
| Autor: | Naveed Altaf Malik, Sheraz Jamal Khan, Sebahattin Cirak, Ayaz Khan, Maria Iqbal, Saif ul Haque, Janine Altmüller, Muhammad Tariq, Muhammad Sajid Hussain, Syeda Seema Waseem, Birgit Budde, Holger Thiele, Shahid Mahmood Baig, Peter Nürnberg, Abubakar Moawia, Zafar Ali |
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| Rok vydání: | 2021 |
| Předmět: |
Male
Candidate gene Microcephaly Adolescent Genetic Linkage QH426-470 Biology Article Frameshift mutation Exon Genetic linkage Intellectual Disability AKNA Exome Sequencing Genetics medicine Humans Genetic Predisposition to Disease Pakistan Child Frameshift Mutation Peptide sequence Gene Genetics (clinical) Centrosome Cerebral Cortex Homozygote Genetic disorder whole-exome sequencing (WES) Nuclear Proteins medicine.disease Pedigree DNA-Binding Proteins linkage/haplotype analysis Haplotypes Female autosomal recessive primary microcephaly (MCPH) Technology Platforms Transcription Factors |
| Zdroj: | Genes Volume 12 Issue 10 Genes, Vol 12, Iss 1494, p 1494 (2021) |
| ISSN: | 2073-4425 |
| DOI: | 10.3390/genes12101494 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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