Microcephaly And Chorioretinopathy, Autosomal Recessive, 2

A number sign (#) is used with this entry because of evidence that autosomal recessive microcephaly and chorioretinopathy-2 (MCCRP2) is caused by homozygous mutation in the PLK4 gene (605031) on chromosome 4q28.

Description

Microcephaly and chorioretinopathy-2 is an autosomal recessive developmental disorder characterized by delayed psychomotor development, visual impairment, and short stature (summary by Martin et al., 2014).

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

Clinical Features

Martin et al. (2014) reported 7 members of a highly consanguineous Pakistani family with a severe developmental disorder characterized by primary microcephaly (up to -15 SD), profoundly delayed psychomotor development, and growth retardation with dwarfism (up to -8 SD). Many patients had ocular abnormalities, including microphthalmia, microcornea, and cataracts. More detailed ophthalmologic studies were not performed. Neuroimaging in some patients showed a marked reduction in cortical size with simplified gyral folding, small cerebellum, and small brainstem. Two additional patients with a similar phenotype were subsequently identified. Detailed ophthalmologic examination of one showed pale optic discs, thin retinal vessels, bilateral macular atrophy, and severe generalized retinopathy.

Shaheen et al. (2014) reported 3 members of a consanguineous Saudi Arabian family with global developmental delay, short stature, microcephaly, and optic nerve hypoplasia with strabismus. Two sibs aged 40 months and 19 months were described in detail: heights were -7.2 SD and -6.4 SD, and head circumferences were -10.1 SD and -11.8 SD, respectively. Facial features included sloping forehead, prominent nose, prominent eyes, and micrognathia; 1 had prominent metopic sutures. The third affected family member had similar features. Shaheen et al. (2014) noted the phenotypic similarities to Seckel syndrome (SCKL1; 210600).

Inheritance

The transmission pattern of MCCRP2 in the families reported by Martin et al. (2014) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 7 individuals from a highly consanguineous Pakistani family with MCCRP2, Martin et al. (2014) identified a homozygous truncating mutation in the PLK4 gene (605031.0001). The mutation, which was found by exome sequencing, segregated with the disorder in the family. An unrelated patient from Madagascar with a similar disorder who underwent exome sequencing was found to carry a different truncating mutation in the PLK4 gene (605031.0002). Direct sequencing of the PLK4 gene in 318 patients with primary microcephaly and primordial dwarfism identified 1 Iranian patient with the same truncating mutation as the patient from Madagascar. Patient fibroblasts showed a significant reduction in centriole number and impaired spindle formation during mitosis compared to controls. Patient fibroblasts also showed a decrease in the number of ciliated cells, and cilia loss correlated with the absence of basal bodies, although the patients did not show a ciliopathy phenotype. The findings provided a mechanism for the poor growth and microcephaly observed in the patients.

In 3 members of a consanguineous Saudi Arabian family with autosomal recessive MCCRP2, Shaheen et al. (2014) identified a homozygous truncating mutation in the PLK4 gene (605031.0003). The mutation, which was found by a combination of homozygosity mapping and candidate gene sequencing, segregated with the disorder in the family. Patient cells were not available for functional studies, but the mutation was predicted to completely abolish the cryptic polo-box domain, resulting in deficient centriole assembly.

Animal Model

Martin et al. (2014) found that morpholino knockdown of plk4 in zebrafish resulted in a smaller body size due to decreased cell proliferation. There was evidence of a delay in mitotic progression with impaired centriole duplication and impaired spindle formation. Mutant zebrafish had a variable reduction in eye size and impaired responses to visual stimuli associated with a loss of cells containing cilia and an absence of basal bodies in the photoreceptor layer. Plk4-null animals also showed a ciliary phenotype, with hydrocephalus, renal cysts, ventral curvature, and left-right asymmetry defects.