Biallelic variants in AGTPBP1, involved in tubulin deglutamylation, are associated with cerebellar degeneration and motor neuropathy.
Alleles
Amino Acid Substitution
Child, Preschool
Consanguinity
DNA Mutational Analysis
Female
GTP-Binding Proteins
/ genetics
Humans
Infant
Magnetic Resonance Imaging
Male
Motor Neuron Disease
/ diagnostic imaging
Mutation
Neurodegenerative Diseases
/ diagnostic imaging
Serine-Type D-Ala-D-Ala Carboxypeptidase
/ genetics
Spinocerebellar Degenerations
/ diagnostic imaging
Tubulin
/ metabolism
Exome Sequencing
Journal
European journal of human genetics : EJHG
ISSN: 1476-5438
Titre abrégé: Eur J Hum Genet
Pays: England
ID NLM: 9302235
Informations de publication
Date de publication:
09 2019
09 2019
Historique:
received:
26
10
2018
accepted:
26
03
2019
revised:
16
03
2019
pubmed:
13
4
2019
medline:
13
6
2020
entrez:
13
4
2019
Statut:
ppublish
Résumé
The ATP/GTP-Binding Protein 1 (AGTPBP1) gene (OMIM *606830) catalyzes deglutamylation of polyglutamylated proteins, and its deficiency manifests by cerebellar ataxia and peripheral neuropathy in mice and lower motor neuron-like disease in sheep. In the mutant mice, cerebellar atrophy due to Purkinje cell degeneration is observed, likely due to increased tubulin polyglutamylation in affected brain areas. We report two unrelated individuals who presented with early onset cerebellar atrophy, developmental arrest with progressive muscle weakness, and feeding and respiratory difficulties, accompanied by severe motor neuronopathy. Whole exome sequencing followed by segregation analysis in the families and cDNA studies revealed deleterious biallelic variants in the AGTPBP1 gene. We conclude that complete loss-of-function of AGTPBP1 in humans, just like in mice and sheep, is associated with cerebellar and motor neuron disease, reminiscent of Pontocerebellar Hypoplasia Type 1 (PCH1).
Identifiants
pubmed: 30976113
doi: 10.1038/s41431-019-0400-y
pii: 10.1038/s41431-019-0400-y
pmc: PMC6777529
doi:
Substances chimiques
Tubulin
0
AGTPBP1 protein, human
EC 3.4.16.4
Serine-Type D-Ala-D-Ala Carboxypeptidase
EC 3.4.16.4
GTP-Binding Proteins
EC 3.6.1.-
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1419-1426Références
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