Abnormal centrosome and spindle morphology in a patient with autosomal recessive primary microcephaly type 2 due to compound heterozygous WDR62 gene mutation

Heba Gamal Farag,Angela Huebner,Ethiraj Ravindran,Konrad Oexle,Detlev Schindler,Angela M Kaindl,Timo Staab,Nadine Kraemer,Sebastian Froehler,Wei Chen

doi:10.1186/1750-1172-8-178

Abstract

BackgroundAutosomal recessive primary microcephaly (MCPH) is a rare neurodevelopmental disease with severe microcephaly at birth due to a pronounced reduction in brain volume and intellectual disability. Biallelic mutations in the WD repeat-containing protein 62 gene WDR62 are the genetic cause of MCPH2. However, the exact underlying pathomechanism of MCPH2 remains to be clarified.Methods/resultsWe characterized the clinical, radiological, and cellular features that add to the human MCPH2 phenotype. Exome sequencing followed by Sanger sequencing in a German family with two affected daughters with primary microcephaly revealed in the index patient the compound heterozygous mutations c.1313G>A (p.R438H) / c.2864-2867delACAG (p.D955Afs*112) of WDR62, the second of which is novel. Radiological examination displayed small frontal lobes, corpus callosum hypoplasia, simplified hippocampal gyration, and cerebellar hypoplasia. We investigated the cellular phenotype in patient-derived lymphoblastoid cells and compared it with that of healthy female controls. WDR62 expression in the patient’s immortalized lymphocytes was deranged, and mitotic spindle defects as well as abnormal centrosomal protein localization were apparent.ConclusionWe propose that a disruption of centrosome integrity and/or spindle organization may play an important role in the development of microcephaly in MCPH2.

Highlights

Autosomal recessive primary microcephaly (MCPH) is a rare neurodevelopmental disorder that results in severe microcephaly at birth with reduction in brain volume, simplified neocortical gyration, and intellectual disability [1,2,3]
We propose that a disruption of centrosome integrity and/or spindle organization may play an important role in the development of microcephaly in MCPH2
We searched for autosomal-dominant, autosomal-recessive homozygous, compound heterozygous, and de novo mutations. Through this exome sequencing approach, we identified two compound heterozygous mutations of the WD repeat-containing protein 62 (WDR62) gene in the index patient: (i) a missense mutation (c.1313G>A) in exon 10 that was inherited from the mother and resulted in a substitution of arginine by histidine (R438H); (ii) a frameshift mutation with deletion of 4 nucleotides (c.2864-2867delACAG) in exon 23 that was inherited from the father and resulted in a stop codon of the new reading frame 112 aa downstream of the deletion (D955Afs*112)

Summary

Introduction

Autosomal recessive primary microcephaly (MCPH) is a rare neurodevelopmental disorder that results in severe microcephaly at birth with reduction in brain volume, simplified neocortical gyration, and intellectual disability [1,2,3]. WDR62 is essential for mitotic spindle stabilization during mitosis and, as demonstrated in HeLa cells, it accumulates at the centrosome or the nucleus in a cell-cycle-dependent manner (from late prophase until metaphase-anaphase transition) [13]. It is enriched in proliferating precursors of the neuroepithelium in the developing murine brain [4,7] but at the same time it is present in the cortical plate, a region where (postmitotic) neurons reside [12]. The exact underlying pathomechanism of MCPH2 remains to be clarified

Results

Discussion

Conclusion