PRDM10 directs FLCN expression in a novel disorder overlapping with Birt–Hogg–Dubé syndrome and familial lipomatosis
In: Human Molecular Genetics, Jg. 32 (2022), Heft 7, S. 1223-1235
Online
academicJournal
Zugriff:
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.
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PRDM10 directs FLCN expression in a novel disorder overlapping with Birt–Hogg–Dubé syndrome and familial lipomatosis
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Autor/in / Beteiligte Person: | van de Beek, Irma ; Glykofridis, Iris E ; Oosterwijk, Jan C ; van den Akker, Peter C ; Diercks, Gilles F H ; Bolling, Maria C ; Waisfisz, Quinten ; Mensenkamp, Arjen R ; Balk, Jesper A ; Zwart, Rob ; Postma, Alex V ; Meijers-Heijboer, Hanne E J ; van Moorselaar, R Jeroen A ; Wolthuis, Rob M F ; Houweling, Arjan C ; Cancer Center Amsterdam ; Amsterdam University Medical Centers |
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Zeitschrift: | Human Molecular Genetics, Jg. 32 (2022), Heft 7, S. 1223-1235 |
Veröffentlichung: | Oxford University Press (OUP), 2022 |
Medientyp: | academicJournal |
ISSN: | 0964-6906 |
DOI: | 10.1093/hmg/ddac288 |
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