23 September 2020
New genetic mutations behind microcephaly identified
Published online 3 May 2015
New study advances understanding of the genetic bases for “small brains," a neurodevelopmental disorder that hampers intellectual abilities.
Researchers have discovered novel genetic mutations that cause microcephaly, a condition in which the brain fails to achieve normal size, resulting in decreased volume of white matter and intellectual disability.
The research team sequenced the genomes of children with microcephaly from consanguineous Omani and Palestinian families, identifying two novel mutations in the PYCR2 gene, which codes an enzyme with an important role in proper brain development1.
To tie PYCR2 gene mutations to microcephaly, the scientists mimicked PYCR2 gene loss and PYCR2 enzyme deficiency in zebrafish. They found that blocking the function of a gene homologous to PYCR2 gene led to microcephaly in zebrafish.
Next, the researchers expressed a mutated PYCR2 gene in cultured human cells. They found that the cells with the mutated PYCR2 gene had reduced levels of PYCR2 enzyme compared with their normal counterparts. The mutated cells were also more susceptible to oxidative-stress-induced death than those carrying the normal PYCR2 gene. This vulnerability of the cells lacking the normal PYCR2 gene suggests a possible mechanism of cell death in microcephaly.
“This study will help clinicians worldwide to make clinical and molecular diagnoses in patients with microcephaly. Since this condition affects a metabolic pathway, maybe it will be feasible to develop a treatment for this condition," says principal investigator Ganeshwaran Mochida from Boston Children’s Hospital, USA.
- Nakayama, T. et al. Mutations in PYCR2, encoding pyrroline-5-carboxylate reductase 2, cause microcephaly and hypomyelination. Am. J. Hum. Genet. http://dx.doi.org/10.1016/j.ajhg.2015.03.003 (2015).