Two Stories of Neurodevelopment: Exosome-Mediated Secretion of Sonic Hedgehog and Somatic Mutation in Disorders of DNA Damage Repair

Abstract

Human genetics of neonatal brain malformations has identified dozens of genes required for brain development that regulate diverse cellular processes. Recent evidence shows that somatic mutations, mutations that are only present in some cells of the body, can also cause brain malformations and disease. We have studied the function of a recently identified microcephaly and cerebellar hypoplasia gene, CHMP1A, and found that it is required for exosome-mediated secretion of sonic hedgehog (SHH). SHH is an essential growth factor in the developing brain, and our results reveal a novel mechanism for SHH secretion in the vertebrate brain. Somatic mutations are caused by incorrect repair of damaged DNA. Cockayne syndrome and xeroderma pigmentosum are disorders of DNA damage repair that cause microcephaly and early neurodegeneration. Using whole genome sequencing, we measured somatic mutation rate in post-mortem single cortical neurons from patients with these disorders and found a dramatic increase in the number of somatic mutations compared to normal individuals.