Biallelic variants in PSMB1 encoding the proteasome subunit ß6 cause impairment of proteasome function, microcephaly, intellectual disability, developmental delay and short stature.
Hum Mol Genet
; 29(7): 1132-1143, 2020 05 08.
Article
em En
| MEDLINE
| ID: mdl-32129449
ABSTRACT
The molecular cause of the majority of rare autosomal recessive disorders remains unknown. Consanguinity due to extensive homozygosity unravels many recessive phenotypes and facilitates the detection of novel gene-disease links. Here, we report two siblings with phenotypic signs, including intellectual disability (ID), developmental delay and microcephaly from a Pakistani consanguineous family in which we have identified homozygosity for p(Tyr103His) in the PSMB1 gene (Genbank NM_002793) that segregated with the disease phenotype. PSMB1 encodes a ß-type proteasome subunit (i.e. ß6). Modeling of the p(Tyr103His) variant indicates that this variant weakens the interactions between PSMB1/ß6 and PSMA5/α5 proteasome subunits and thus destabilizes the 20S proteasome complex. Biochemical experiments in human SHSY5Y cells revealed that the p(Tyr103His) variant affects both the processing of PSMB1/ß6 and its incorporation into proteasome, thus impairing proteasome activity. CRISPR/Cas9 mutagenesis or morpholino knock-down of the single psmb1 zebrafish orthologue resulted in microcephaly, microphthalmia and reduced brain size. Genetic evidence in the family and functional experiments in human cells and zebrafish indicates that PSMB1/ß6 pathogenic variants are the cause of a recessive disease with ID, microcephaly and developmental delay due to abnormal proteasome assembly.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Complexo de Endopeptidases do Proteassoma
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Nanismo
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Microcefalia
Limite:
Animals
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Child
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Female
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Humans
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Male
Idioma:
En
Revista:
Hum Mol Genet
Assunto da revista:
BIOLOGIA MOLECULAR
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GENETICA MEDICA
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
Suíça