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Of mice and men

13 Dec 2017

A rare mutation causes severe growth retardation and spine malformation in humans and mice

A*STAR researchers have uncovered a genetic mutation that causes severe growth retardation in humans and mice.

A*STAR researchers have uncovered a genetic mutation that causes severe growth retardation in humans and mice.

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Mutations in a gene associated with cellular proliferation cause a previously unknown disease characterized by severe growth retardation, spine malformation, dysmorphic facial features and intellectual disabilities, according to an international study led by A*STAR researchers.

The team found that nine individuals from five unrelated families in Turkey, Algeria, Tunisia and Saudi Arabia with identical clinical features all carry mutations that inactivate the cyclin-dependent kinase 10 (CDK10) gene. Mutations are rare in CDK genes, which encode proteins that regulate cell growth and division and are carefully kept in check to prevent tumor formation.

To investigate the effects of losing the function of CDK10, the researchers generated mice lacking the Cdk10 gene. These mice displayed severe growth retardation and some skeletal defects that resemble those observed in patients with CDK10 mutations, or what has been termed Al Kaissi Syndrome. “The mouse model provides compelling data that CDK10 is the gene causing disease, and confirms the human genetic data” said Philipp Kaldis, at the A*STAR Institute of Molecular and Cell Biology and lead author of the study.

Despite Cdk10 being an essential gene for mouse development, fibroblast cells from Cdk10-deficient mice and from patients divided normally when isolated and grown in the lab. However, analyses of various organs revealed multiple defects in the mice lacking Cdk10. In the affected organs (which included kidneys, lungs, brain, intestine and muscle) more than 600 genes were expressed differently compared with healthy control mice. A significant number of these genes are involved in lipid metabolism which suggests that the impaired conversion of fats into energy may underlie the growth retardation observed in mice and humans bearing CDK10 mutations. This raises the potential for mitigating some of the features associated with Al Kaissi Syndrome through dietary interventions.

The expression of genes involved in the formation of tiny hair-like, sensory cellular protrusions called cilia was affected in organs of Cdk10-deficient mice — their fibroblasts developed longer cilia than the healthy controls. The functional consequences of Cdk10’s effect on cilia, however, remain to be investigated.

This study is a great example of how mouse models contribute to our understanding of human developmental disorders. “Without the mouse model that recapitulates some of the features of Al Kaissi Syndrome we would not have uncovered a new role for CDK10 in cilia growth and metabolism” explains Kaldis.

Identifying the genetic causes of rare conditions not only helps physicians with diagnoses, but offers researchers a starting point for developing new treatments.

The A*STAR-affiliated researchers contributing to this research are from the Institute of Medical Biology and the Institute of Molecular and Cell Biology. For more information about the team’s research, please visit the Kaldis and Reversade webpages.

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Windpassinger, C., Piard, J., Bonnard, C., Alfadhel, M., Lim, S. et al. CDK10 mutations in humans and mice cause severe growth retardation, spine malformations and developmental delays. The American Journal of Human Genetics 101, 391–403 (2017). | Article

This article was made for A*STAR Research by Nature Research Custom Media, part of Springer Nature