In the Journal of Clinical Investigation, researchers have reported a rare neurodevelopmental condition characterised by intellectual disability, ataxia with cerebellar hypoplasia and delayed puberty with hypogonadotropic hypogonadism (HH).
Patients with this unusual combination of conditions were referred to Mehul Dattani (UCL), and affected individuals were found to carry the same homozygous mutation in the PRDM13 gene, which encodes a chromatin modifying factor that contributes to regulating cell fate. Intriguingly, an unaffected heterozygous carrier of this mutation was identified by screening 42 unaffected individuals in the Maltese population, suggesting that this mutation is present at low levels in the population.
The researchers set out to model this condition and identify the underlying causes using a PRDM13-deficient mouse model. The researchers found evidence that both the cerebellar hypoplasia and reproductive phenotypes resulted from defects in the specification of specific populations of GABAergic neuronal progenitors in the developing cerebellum and hypothalamus, respectively.
The results indicate that this condition results from abnormal cell fate specification during development. Consequently, the hypoplastic cerebellum is deficient in molecular layer interneurons, which play critical roles in regulating cerebellar circuits. In the hypothalamus, fewer Kisspeptin neurons, which are important regulators of gonadotropin releasing hormone and puberty, were present in PRDM13 mutant mice.
Together, these findings identify PRDM13 as a critical regulator of neuronal cell fate in the cerebellum and hypothalamus, providing a mechanistic explanation for the co-occurrence of hypogonadism and cerebellar hypoplasia in this syndrome.
Source: King’s College London
