Biallelic loss-of-function variants in NEMF cause central nervous system impairment and axonal polyneuropathy.
Adolescent
Adult
Alleles
Animals
Antigens, Neoplasm
/ genetics
Axons
Brain
/ metabolism
Cells, Cultured
Central Nervous System Diseases
/ genetics
Consanguinity
Female
Gene Expression Profiling
Genes, Recessive
Homozygote
Humans
Loss of Function Mutation
Male
Mice, Inbred C57BL
Nucleocytoplasmic Transport Proteins
/ genetics
Pedigree
Polyneuropathies
/ genetics
RNA-Seq
Exome Sequencing
Young Adult
Journal
Human genetics
ISSN: 1432-1203
Titre abrégé: Hum Genet
Pays: Germany
ID NLM: 7613873
Informations de publication
Date de publication:
Apr 2021
Apr 2021
Historique:
received:
15
07
2020
accepted:
28
09
2020
pubmed:
14
10
2020
medline:
31
3
2021
entrez:
13
10
2020
Statut:
ppublish
Résumé
We aimed to detect the causative gene in five unrelated families with recessive inheritance pattern neurological disorders involving the central nervous system, and the potential function of the NEMF gene in the central nervous system. Exome sequencing (ES) was applied to all families and linkage analysis was performed on family 1. A minigene assay was used to validate the splicing effect of the relevant discovered variants. Immunofluorescence (IF) experiment was performed to investigate the role of the causative gene in neuron development. The large consanguineous family confirms the phenotype-causative relationship with homozygous frameshift variant (NM_004713.6:c.2618del) as revealed by ES. Linkage analysis of the family showed a significant single-point LOD of 4.5 locus. Through collaboration in GeneMatcher, four additional unrelated families' likely pathogenic NEMF variants for a spectrum of central neurological disorders, two homozygous splice-site variants (NM_004713.6:c.574+1G>T and NM_004713.6:c.807-2A>C) and a homozygous frameshift variant (NM_004713.6: c.1234_1235insC) were subsequently identified and segregated with all affected individuals. We further revealed that knockdown (KD) of Nemf leads to impairment of axonal outgrowth and synapse development in cultured mouse primary cortical neurons. Our study demonstrates that disease-causing biallelic NEMF variants result in central nervous system impairment and other variable features. NEMF is an important player in mammalian neuron development.
Identifiants
pubmed: 33048237
doi: 10.1007/s00439-020-02226-3
pii: 10.1007/s00439-020-02226-3
doi:
Substances chimiques
Antigens, Neoplasm
0
NEMF protein, human
0
Nucleocytoplasmic Transport Proteins
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
579-592Subventions
Organisme : National Natural Science Foundation of China
ID : 81730036
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