A Homozygous AKNA Frameshift Variant Is Associated with Microcephaly in a Pakistani Family.

Syeda Seema Waseem,Saif Ul Haque,Muhammad Tariq,Shahid Mahmood Baig,Muhammad Sajid Hussain,Maria Iqbal,Zafar Ali,Abubakar Moawia,Naveed Altaf Malik,Holger Thiele,Birgit Budde,Janine Altmüller,Peter Nürnberg,Sebahattin Cirak,Ayaz Khan,Sheraz Khan

doi:10.3390/genes12101494

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.

Highlights

Autosomal recessive primary microcephaly (MCPH, for “microcephaly primary hereditary”) is a rare neurodevelopmental disorder characterized by a reduced head circumference (HC) with more than three standard deviations (SD) below the mean for the same age and sex
More detailed investigations on this rare syndrome can divulge the common molecular pathways necessary for the maintenance and regulation of neural progenitor cells (NPCs) that are responsible for determining the cerebral cortex size and human brain evolution
Our finding is in keeping with the observation that most MCPH-associated genes are coding for centrosomal proteins [4,25,26,27]

Summary

Introduction

Autosomal recessive primary microcephaly (MCPH, for “microcephaly primary hereditary”) is a rare neurodevelopmental disorder characterized by a reduced head circumference (HC) with more than three standard deviations (SD) below the mean for the same age and sex. 28 genes have been reported for MCPH with ASPM (MCPH5) and WDR62 (MCPH2) as the most frequently mutated genes in approximately 50% and 14% of all studied families, respectively [7,8,9,10] Many of these MCPH genes encode centrosomal proteins that are essentially needed in centriole biogenesis [11]. Others are known to be implicated in diverse mechanistic pathways such as DNA replication and repair, cytokinesis, kinetochore function, Wnt signaling, transmembrane or intracellular transport [12]. It suggests a diverse involvement of molecular and cellular mechanisms in controlling the cerebral cortex size during brain development. More detailed investigations on this rare syndrome can divulge the common molecular pathways necessary for the maintenance and regulation of neural progenitor cells (NPCs) that are responsible for determining the cerebral cortex size and human brain evolution

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Conclusion