CDK5RAP2 – autosomal recessive primary microcephaly

Autosomal recessive primary microcephaly (MCPH) due to biallelic CDK5RAP2 mutations (MCPH3) is characterized by congenital reduced head circumference, simplified gyral pattern, hypogenesis of the corpus callosum and intellectual disability. Initial reports described homozygosity for a novel nonsense variant c.4441C>T (p.Arg1481Ter) in two Italian siblings with linkage to MCPH3 ([PMID:23587236]). A subsequent case identified compound heterozygous LoF alleles (c.524_528del [p.Gln175fs] and c.4005-1G>A) in a non-consanguineous Caucasian proband, expanding the genetic and ethnic spectrum ([PMID:23726037]). Together with additional consanguineous families segregating homozygous truncating variants (e.g., c.448C>T [p.Arg150Ter]) in multiple affected individuals, at least six unrelated probands from four pedigrees support a robust genotype–phenotype correlation with CDK5RAP2 and MCPH ([PMID:35035405]).

Inheritance is uniformly autosomal recessive, with homozygous or compound heterozygous loss-of-function variants abolishing CDK5RAP2 expression. Segregation analysis has demonstrated co-segregation of pathogenic alleles in at least four affected relatives across two families (2 siblings in the Italian kindred and 2 siblings in a Pakistani MCPH family) ([PMID:23587236]; [PMID:35035405]).

Functional studies in patient-derived lymphoblastoid cells reveal undetectable CDK5RAP2 protein levels, spindle pole abnormalities and disrupted γ-tubulin localization, implicating centrosome integrity defects in pathogenesis ([PMID:23587236]). Mouse Cdk5rap2(an/an) models faithfully recapitulate microcephaly through premature cell-cycle exit, neuroprogenitor apoptosis and mitotic spindle disorganization, confirming haploinsufficiency as the mechanism ([PMID:20460369]). Additionally, biochemical assays demonstrate CDK5RAP2 binding to EB1 at microtubule plus-ends, regulating microtubule dynamics essential for neuronal precursor proliferation ([PMID:19553473]).

No credible conflicting evidence has been reported for CDK5RAP2 in MCPH3. All variants are absent or extremely rare in population databases and consistent with loss-of-function intolerance.

In summary, multiple independent families with recessive LoF variants and concordant functional data establish a Strong gene–disease relationship between CDK5RAP2 and autosomal recessive primary microcephaly. CDK5RAP2 mutation screening should be considered in MCPH diagnostics, carrier testing and genetic counselling.

Key Take-home: Biallelic loss-of-function variants in CDK5RAP2 cause MCPH3 via centrosome-mediated neurogenic mitotic failure, with clear implications for diagnosis and family planning.

References

• Orphanet journal of rare diseases | 2013 | Clinical and cellular features in patients with primary autosomal recessive microcephaly and a novel CDK5RAP2 mutation. [PMID:23587236]
• Brain & development | 2014 | The first case of CDK5RAP2-related primary microcephaly in a non-consanguineous patient identified by next generation sequencing. [PMID:23726037]
• Development (Cambridge, England) | 2010 | Cdk5rap2 regulates centrosome function and chromosome segregation in neuronal progenitors. [PMID:20460369]
• Molecular biology of the cell | 2009 | Interaction of CDK5RAP2 with EB1 to track growing microtubule tips and to regulate microtubule dynamics. [PMID:19553473]

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