Clinical, genetic, and molecular characteristics in a central‐southern Chinese cohort of genetic leukodystrophies

OBJECTIVE: Leukodystrophies are a diverse group of rare inherited disorders that affect the white matter of the central nervous system with a wide phenotypic spectrum. We aimed to characterize the clinical and genetic features of leukodystrophies in a central‐southern Chinese cohort. METHODS: A cohort of 16 Chinese probands with leukodystrophy was recruited and performed genetic analysis by targeted panels or whole‐exome sequencing. Further functional analysis of identified mutations in the colony stimulating factor 1 receptor (CSF1R) gene was explored. RESULTS: A total of eight pathogenic variants (3 novel, 5 documented) were identified in genes including AARS2, ABCD1, CSF1R, and GALC. Common symptoms of leukodystrophy such as cognitive decline, behavioral symptoms, bradykinesia, and spasticity were observed in mutation carriers as well as other rare features (e.g., seizure, dysarthric, and vision impairment). Overexpressing CSF1R mutants p.M875I and p.F971Sfs*7 in vitro showed pronounced cleavage CSF1R and suppressed protein expression, respectively, and reduced transcripts of both mutants were observed. CSF1 treatment revealed deficient and suppressed CSF1R phospho‐activation with the mutants. In contrast to the plasma membrane and endoplasmic reticulum (ER) localized wild‐type CSF1R, M875I mutant showed much less membrane association and greater detainment in the ER, whereas F971Sfs*7 mutation led to aberrant non‐ER localization. Both mutations caused suppressed cell viability, which was partially resulted from deficient/suppressed CSF1R‐ERK signaling. INTERPRETATION: In summary, our findings expand the mutation spectrum of these genes in leukodystrophies. Supported by in vitro validation of the pathogenicity of heterozygous CSF1R mutations, our data also provide insights into the pathogenic mechanisms of CSF1R‐related leukodystrophy.