Congenital microcephaly-linked CDK5RAP2 affects eye development.

Sami Zaqout,Gisela Stoltenburg‐Didinger,Ethiraj Ravindran,Angela M Kaindl

doi:10.1111/ahg.12343

Sami Zaqout, Gisela Stoltenburg‐Didinger + Show 2 more

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https://doi.org/10.1111/ahg.12343

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Abstract

Biallelic mutations in the cyclin-dependent kinase 5 regulatory subunit-associated protein 2 gene CDK5RAP2 cause autosomal recessive primary microcephaly type 3 (MCPH3). MCPH is characterized by intellectual disability and microcephaly at birth, classically without further organ involvement. Only recently, congenital cataracts were reported in four patients of one pedigree with MCPH3. Given the lack of a further pedigree with this phenotype, it remained unclear whether this was a true causal relationship. Here we support the link between CDK5RAP2 and eye development by showing that most Cdk5rap2 mutant mice (an/an) exhibit eye malformations ranging from reduced size of one or both eyes (microphthalmia) to total absence of both eyes (anophthalmia). We also detected increased apoptosis in the an/an retinal progenitor cells associated with more mitotic cells. This indicates an important role of Cdk5rap2 in physiologic eye development.

Highlights

Biallelic mutations in the cyclin-dependent kinase 5 regulatory subunit-associated protein 2 gene CDK5RAP2 cause autosomal-recessive primary microcephaly type 3 (MCPH3)
We support the link between CDK5RAP2 and eye development by showing that most Cdk5rap2 mutant mice exhibit eye malformations ranging from reduced size of one or both eyes to total absence of both eyes
We looked for potential defects in the proliferation and/or apoptosis in RPCs that might lead to the resultant eye phenotype in an/an

Summary

Introduction

Biallelic mutations in the cyclin-dependent kinase 5 regulatory subunit-associated protein 2 gene CDK5RAP2 cause autosomal-recessive primary microcephaly type 3 (MCPH3) (reviewed in Kraemer et al, 2011; Zaqout, Morris-Rosendahl, & Kaindl, 2017b). Patients with MCPH3 display nonprogressive microcephaly at birth and nonsyndromic intellectual disability, classically without further organ involvement (Kaindl et al, 2010). Congenital cataracts were reported in four patients of one pedigree with MCPH3 (Alfares et al, 2018; Pagnamenta et al, 2012). Cdk5rap mutant or Hertwig’s anemia mice (an/an) show congenital microcephaly, peripheral blood cytopenia, spontaneous aneuploidy, predisposition to hematopoietic tumors, and lack of germ cells leading to infertility

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