Microcephaly And Chorioretinopathy, Autosomal Recessive, 3

A number sign (#) is used with this entry because of evidence that autosomal recessive microcephaly and chorioretinopathy-3 (MCCRP3) is caused by compound heterozygous mutation in the TUBGCP4 gene (609610) on chromosome 15q15.

For a discussion of genetic heterogeneity of microcephaly and chorioretinopathy, see MCCRP1 (251270).

Clinical Features

Scheidecker et al. (2015) reported 4 children from 3 unrelated French families with congenital microcephaly and chorioretinal dysplasia associated with poor vision and nystagmus. Fundus examination showed multiple punched-out retinal lesions. More variable ocular anomalies included microphthalmia, retinal folding, retinal detachment, optic nerve hypoplasia, absence of retinal vessels, round areas of chorioretinal atrophy, and attenuated electroretinogram. Most patients had mildly delayed development and mild learning difficulties, but no other significant neurologic abnormalities. Brain MRI was normal in 3 patients; 1 patient had a thin corpus callosum. Two sibs had mild dysmorphic facial features, including downslanting palpebral fissures, large ears, and mild retrognathia.

Inheritance

The transmission pattern of MCCRP3 in the families reported by Scheidecker et al. (2015) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 4 French children from 3 unrelated families with autosomal recessive microcephaly and chorioretinopathy-3, Scheidecker et al. (2015) identified compound heterozygous mutations in the TUBGCP4 gene (609610.0001-609610.0004). Mutations in the first 2 families were found by exome sequencing; mutations in the third family were found by Sanger sequencing of 12 additional French patients with a similar disorder. Detailed studies of fibroblasts derived from 1 patient showed reduced amounts of both TUBGCP4 protein and other components of the gamma-tubulin complex. Patient cells showed reduced levels of microtubule nucleation after depolymerization, abnormal microtubule organization, changes in cell shape, and abnormally shaped nuclei indicating aneuploid cells resulting from defects in cytokinesis late in mitosis.

Animal Model

Scheidecker et al. (2015) found that morpholino knockdown of the tubgcp4 ortholog in zebrafish embryos resulted in smaller head and eyes as well as shortened body axis in most embryos compared to controls. The retina of mutant zebrafish was punctuated with rounded cells and showed cone and rod photoreceptor changes suggestive of impaired differentiation.