PRDM10 directs FLCN expression in a novel disorder overlapping with Birt-Hogg-Dubé syndrome and familial lipomatosis.
Humans
Birt-Hogg-Dube Syndrome
/ genetics
Carcinoma, Renal Cell
/ genetics
Genes, Tumor Suppressor
Skin Neoplasms
/ genetics
Lipomatosis
/ genetics
Kidney Neoplasms
/ genetics
DNA-Binding Proteins
/ genetics
Transcription Factors
/ genetics
Proto-Oncogene Proteins
/ genetics
Tumor Suppressor Proteins
/ genetics
Journal
Human molecular genetics
ISSN: 1460-2083
Titre abrégé: Hum Mol Genet
Pays: England
ID NLM: 9208958
Informations de publication
Date de publication:
20 03 2023
20 03 2023
Historique:
received:
22
02
2022
revised:
05
11
2022
accepted:
19
11
2022
pubmed:
29
11
2022
medline:
22
3
2023
entrez:
28
11
2022
Statut:
ppublish
Résumé
Birt-Hogg-Dubé syndrome (BHD) is an autosomal dominant disorder characterized by fibrofolliculomas, pulmonary cysts, pneumothoraces and renal cell carcinomas. Here, we reveal a novel hereditary disorder in a family with skin and mucosal lesions, extensive lipomatosis and renal cell carcinomas. The proband was initially diagnosed with BHD based on the presence of fibrofolliculomas, but no pathogenic germline variant was detected in FLCN, the gene associated with BHD. By whole exome sequencing we identified a heterozygous missense variant (p.(Cys677Tyr)) in a zinc-finger encoding domain of the PRDM10 gene which co-segregated with the phenotype in the family. We show that PRDM10Cys677Tyr loses affinity for a regulatory binding motif in the FLCN promoter, abrogating cellular FLCN mRNA and protein levels. Overexpressing inducible PRDM10Cys677Tyr in renal epithelial cells altered the transcription of multiple genes, showing overlap but also differences with the effects of knocking out FLCN. We propose that PRDM10 controls an extensive gene program and acts as a critical regulator of FLCN gene transcription in human cells. The germline variant PRDM10Cys677Tyr curtails cellular folliculin expression and underlies a distinguishable syndrome characterized by extensive lipomatosis, fibrofolliculomas and renal cell carcinomas.
Identifiants
pubmed: 36440963
pii: 6849546
doi: 10.1093/hmg/ddac288
pmc: PMC10026250
doi:
Substances chimiques
PRDM10 protein, human
0
DNA-Binding Proteins
0
Transcription Factors
0
FLCN protein, human
0
Proto-Oncogene Proteins
0
Tumor Suppressor Proteins
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1223-1235Informations de copyright
© The Author(s) 2022. Published by Oxford University Press.
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