CNP deficiency causes severe hypomyelinating leukodystrophy in humans

Human Genetics
Lama Al-AbdiFowzan S Alkuraya

Abstract

Myelin pathologies are an important cause of multifactorial, e.g., multiple sclerosis, and Mendelian, e.g., leukodystrophy, neurological disorders. CNP encodes a major component of myelin and its CNS expression is exclusive to myelin-forming oligodendrocytes. Deficiency of CNP in mouse causes a lethal white matter neurodegenerative phenotype. However, a corresponding human phenotype has not been described to date. Here, we describe a multiplex consanguineous family from Oman in which multiple affected members display a remarkably consistent phenotype of neuroregression with profound brain white matter loss. A novel homozygous missense variant in CNP was identified by combined autozygome/exome analysis. Immunoblot analysis suggests that this is a null allele in patient fibroblasts, which display abnormal F-actin organization. Our results suggest the establishment of a novel CNP-related hypomyelinating leukodystrophy in humans.

References

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May 28, 2019·American Journal of Human Genetics·Dorota MoniesFowzan S Alkuraya

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Citations

Sep 26, 2020·Frontiers in Cellular Neuroscience·Olaf JahnHauke B Werner
Dec 17, 2020·Nature Reviews. Neurology·Nicole I WolfMarjo S van der Knaap
Apr 17, 2021·Environment International·Rongbin XuYuming Guo

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Methods Mentioned

BETA
biopsy
genotyping
exome sequencing
electron microscopy
transgenic

Software Mentioned

SIFT
gnomAD
CADD
PolyPhen
Clustal Omega
ImageJ

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