{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,26]],"date-time":"2026-01-26T19:48:15Z","timestamp":1769456895831,"version":"3.49.0"},"reference-count":44,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2021,9,24]],"date-time":"2021-09-24T00:00:00Z","timestamp":1632441600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>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\u2019s 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.<\/jats:p>","DOI":"10.3390\/genes12101494","type":"journal-article","created":{"date-parts":[[2021,9,27]],"date-time":"2021-09-27T04:55:33Z","timestamp":1632718533000},"page":"1494","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["A Homozygous AKNA Frameshift Variant Is Associated with Microcephaly in a Pakistani Family"],"prefix":"10.3390","volume":"12","author":[{"given":"Syeda Seema","family":"Waseem","sequence":"first","affiliation":[{"name":"Cologne Center for Genomics (CCG), Faculty of Medicine, University Hospital Cologne, University of Cologne, 50931 Cologne, Germany"},{"name":"Center for Biochemistry, Medical Faculty, University of Cologne, 50931 Cologne, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abubakar","family":"Moawia","sequence":"additional","affiliation":[{"name":"Cologne Center for Genomics (CCG), Faculty of Medicine, University Hospital Cologne, University of Cologne, 50931 Cologne, Germany"},{"name":"Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine, University Hospital Cologne, University of Cologne, 50931 Cologne, Germany"},{"name":"Department of Pediatrics, Faculty of Medicine, University Hospital Cologne, University of Cologne, 50931 Cologne, Germany"},{"name":"Human Molecular Genetics Laboratory, Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering (NIBGE), PIEAS, Faisalabad 38000, Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9385-4168","authenticated-orcid":false,"given":"Birgit","family":"Budde","sequence":"additional","affiliation":[{"name":"Cologne Center for Genomics (CCG), Faculty of Medicine, University Hospital Cologne, University of Cologne, 50931 Cologne, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5334-403X","authenticated-orcid":false,"given":"Muhammad","family":"Tariq","sequence":"additional","affiliation":[{"name":"Human Molecular Genetics Laboratory, Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering (NIBGE), PIEAS, Faisalabad 38000, Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4743-7387","authenticated-orcid":false,"given":"Ayaz","family":"Khan","sequence":"additional","affiliation":[{"name":"Human Molecular Genetics Laboratory, Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering (NIBGE), PIEAS, Faisalabad 38000, Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2389-3337","authenticated-orcid":false,"given":"Zafar","family":"Ali","sequence":"additional","affiliation":[{"name":"Center for Biotechnology and Microbiology, University of Swat, Swat 19130, Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3207-4074","authenticated-orcid":false,"given":"Sheraz","family":"Khan","sequence":"additional","affiliation":[{"name":"Human Molecular Genetics Laboratory, Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering (NIBGE), PIEAS, Faisalabad 38000, Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria","family":"Iqbal","sequence":"additional","affiliation":[{"name":"Cologne Center for Genomics (CCG), Faculty of Medicine, University Hospital Cologne, University of Cologne, 50931 Cologne, Germany"},{"name":"Center for Biochemistry, Medical Faculty, University of Cologne, 50931 Cologne, Germany"},{"name":"Human Molecular Genetics Laboratory, Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering (NIBGE), PIEAS, Faisalabad 38000, Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Naveed Altaf","family":"Malik","sequence":"additional","affiliation":[{"name":"Human Molecular Genetics Laboratory, Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering (NIBGE), PIEAS, Faisalabad 38000, Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Saif ul","family":"Haque","sequence":"additional","affiliation":[{"name":"Nuclear Medicine, Oncology and Radiotherapy Institute (NORI), PAEC, Islamabad 44000, Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Janine","family":"Altm\u00fcller","sequence":"additional","affiliation":[{"name":"Cologne Center for Genomics (CCG), Faculty of Medicine, University Hospital Cologne, University of Cologne, 50931 Cologne, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Holger","family":"Thiele","sequence":"additional","affiliation":[{"name":"Cologne Center for Genomics (CCG), Faculty of Medicine, University Hospital Cologne, University of Cologne, 50931 Cologne, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1353-8809","authenticated-orcid":false,"given":"Muhammad Sajid","family":"Hussain","sequence":"additional","affiliation":[{"name":"Cologne Center for Genomics (CCG), Faculty of Medicine, University Hospital Cologne, University of Cologne, 50931 Cologne, Germany"},{"name":"Center for Biochemistry, Medical Faculty, University of Cologne, 50931 Cologne, Germany"},{"name":"Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine, University Hospital Cologne, University of Cologne, 50931 Cologne, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sebahattin","family":"Cirak","sequence":"additional","affiliation":[{"name":"Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine, University Hospital Cologne, University of Cologne, 50931 Cologne, Germany"},{"name":"Department of Pediatrics, Faculty of Medicine, University Hospital Cologne, University of Cologne, 50931 Cologne, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shahid Mahmood","family":"Baig","sequence":"additional","affiliation":[{"name":"Human Molecular Genetics Laboratory, Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering (NIBGE), PIEAS, Faisalabad 38000, Pakistan"},{"name":"Pakistan Science Foundation (PSF), 1-Constitution Avenue, G-5\/2, Islamabad 44000, Pakistan"},{"name":"Department of Biological and Biomedical Sciences, Aga Khan University, Karachi 74000, Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7228-428X","authenticated-orcid":false,"given":"Peter","family":"N\u00fcrnberg","sequence":"additional","affiliation":[{"name":"Cologne Center for Genomics (CCG), Faculty of Medicine, University Hospital Cologne, University of Cologne, 50931 Cologne, Germany"},{"name":"Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine, University Hospital Cologne, University of Cologne, 50931 Cologne, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,9,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1038\/s41436-018-0140-3","article-title":"Genomic and phenotypic delineation of congenital microcephaly","volume":"21","author":"Shaheen","year":"2018","journal-title":"Genet. 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