CIT – Autosomal Recessive Primary Microcephaly

Autosomal recessive primary microcephaly (MCPH) is a static neurodevelopmental disorder characterized by congenital small head circumference and non-progressive intellectual disability without additional severe brain malformations. Sixteen genes (MCPH1–MCPH16) have been implicated in MCPH, many encoding proteins that govern mitotic spindle function and cytokinesis. The citron kinase gene CIT encodes CRIK, a Rho-interacting serine/threonine kinase that localizes to the midbody ring during late cytokinesis in proliferating neuroprogenitors. Loss of CIT function leads to binucleation and apoptotic death of neuronal precursors, as demonstrated in both human cells and Cit knockout mice.

In a consanguineous family, genome-wide homozygosity mapping on chromosome 12q24.11–q24.32 followed by exome sequencing in three affected siblings identified a homozygous splice-site variant c.753+3A>T that abolishes the donor site and causes intron retention in CIT, segregating with the MCPH phenotype (three probands) (PMID:27519304).

A separate study described two additional consanguineous families with severe primary microcephaly, spasticity and failure to thrive. Exome sequencing revealed homozygous c.1111+1G>A splice-site and a homozygous missense variant c.4130C>T (p.Pro1377Leu) in CIT; both variants segregated with disease in at least two probands across the families (PMID:27503289).

The variant spectrum in CIT-related MCPH comprises at least two canonical splice-site mutations and one missense change disrupting the kinase domain. All reported variants are rare or absent from control populations and are predicted to result in loss of normal CRIK function.

Functional studies support a haploinsufficient mechanism: loss of CIT expression disrupts cytokinetic abscission in neural precursors, leading to premature cell cycle exit. Knockout mice phenocopy the human MCPH presentation, confirming the critical role of the kinase domain in neurogenic cytokinesis (PMID:27519304, PMID:27503289).

Overall, CIT meets Strong clinical validity criteria for autosomal recessive primary microcephaly: multiple unrelated families, clear segregation, and concordant in vivo and in vitro functional data. Inclusion of CIT in diagnostic gene panels is recommended to improve molecular diagnosis and guide genetic counseling.

References

• Human Genetics • 2016 • CIT, a gene involved in neurogenic cytokinesis, is mutated in human primary microcephaly. PMID:27519304
• Human Genetics • 2016 • Mutations in CIT, encoding citron rho-interacting serine/threonine kinase, cause severe primary microcephaly in humans. PMID:27503289

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