CDK6 – Autosomal Recessive Primary Microcephaly

Autosomal recessive primary microcephaly (MCPH) is characterized by reduced head circumference, a smaller but architecturally normal cerebral cortex and variable intellectual disability. Genetic subtypes map to twelve loci encoding proteins involved in neurogenic mitosis, including cyclin-dependent kinase 6 (CDK6) (PMID:25951892). CDK6 regulates the G1/S cell cycle checkpoint and associates with the centrosome during mitosis, implicating it in spindle orientation critical for neurogenesis.

A consanguineous eight-generation Pakistani family with ten children affected by primary microcephaly underwent homozygosity mapping to 7q21.11-q21.3. Sanger and exome sequencing identified a homozygous c.589G>A (p.Ala197Thr) variant in CDK6 that cosegregated with disease in all ten probands and was absent in ethnically matched controls (PMID:23918663).

The inheritance is autosomal recessive and segregation analysis across ten affected relatives supports co-segregation of the CDK6 variant with MCPH. No additional unrelated families have been reported carrying this variant.

Functional studies in patient-derived fibroblasts harboring p.Ala197Thr revealed supernumerary centrosomes, disorganized microtubules and mitotic spindles, increased centrosome–nucleus distance, reduced proliferation and impaired cell motility and polarity. Ectopic expression of mutant CDK6 and CDK6 knockdown via shRNA recapitulated these defects, establishing concordant cellular phenotypes with the human disease (PMID:23918663).

No studies to date have disputed the CDK6 association with MCPH or described alternative phenotypes for this variant. Larger cohorts and additional familial reports are needed to extend these findings beyond the original kindred.

Collectively, segregation in a large consanguineous family and concordant functional data support a model in which CDK6 p.Ala197Thr impairs centrosome function and neurogenic mitosis, leading to primary microcephaly. Routine inclusion of CDK6 in MCPH diagnostic panels is warranted. Key take-home: CDK6 variants underlie autosomal recessive primary microcephaly and should be screened in affected families.

References

• Human Molecular Genetics • 2013 • CDK6 associates with the centrosome during mitosis and is mutated in a large Pakistani family with primary microcephaly. PMID:23918663
• BMC Medical Genomics • 2015 • Molecular genetics of human primary microcephaly: an overview. PMID:25951892

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