Waseem, Syeda Seema, Moawia, Abubakar, Budde, Birgit, Tariq, Muhammad ORCID: 0000-0002-5334-403X, Khan, Ayaz, Ali, Zafar ORCID: 0000-0002-2389-3337, Khan, Sheraz, Iqbal, Maria, Malik, Naveed Altaf ORCID: 0000-0002-7392-9449, ul Haque, Saif, Altmueller, Janine, Thiele, Holger, Hussain, Muhammad Sajid, Cirak, Sebahattin, Baig, Shahid Mahmood and Nuernberg, Peter (2021). A Homozygous AKNA Frameshift Variant Is Associated with Microcephaly in a Pakistani Family. Genes, 12 (10). BASEL: MDPI. ISSN 2073-4425

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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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Waseem, Syeda SeemaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Moawia, AbubakarUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Budde, BirgitUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tariq, MuhammadUNSPECIFIEDorcid.org/0000-0002-5334-403XUNSPECIFIED
Khan, AyazUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ali, ZafarUNSPECIFIEDorcid.org/0000-0002-2389-3337UNSPECIFIED
Khan, SherazUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Iqbal, MariaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Malik, Naveed AltafUNSPECIFIEDorcid.org/0000-0002-7392-9449UNSPECIFIED
ul Haque, SaifUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Altmueller, JanineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thiele, HolgerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hussain, Muhammad SajidUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cirak, SebahattinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Baig, Shahid MahmoodUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nuernberg, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-592255
DOI: 10.3390/genes12101494
Journal or Publication Title: Genes
Volume: 12
Number: 10
Date: 2021
Publisher: MDPI
Place of Publication: BASEL
ISSN: 2073-4425
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
GENE; MUTATION; SIGNALS; COMPLEX; PROTEIN; MCPH; TOOLMultiple languages
Genetics & HeredityMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/59225

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