Research output: Contribution to journal › Article › Academic › peer-review
PRDM10 directs FLCN expression in a novel disorder overlapping with Birt-Hogg-Dubé syndrome and familial lipomatosis. / van de Beek, Irma; Glykofridis, Iris E; Oosterwijk, Jan C et al.
In: Human molecular genetics, Vol. 32, No. 7, 20.03.2023, p. 1223-1235.Research output: Contribution to journal › Article › Academic › peer-review
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TY - JOUR
T1 - PRDM10 directs FLCN expression in a novel disorder overlapping with Birt-Hogg-Dubé syndrome and familial lipomatosis
AU - van de Beek, Irma
AU - Glykofridis, Iris E
AU - Oosterwijk, Jan C
AU - Akker, Peter C
AU - Diercks, Gilles F H
AU - Bolling, Maria C
AU - Waisfisz, Quinten
AU - Mensenkamp, Arjen R
AU - Balk, Jesper A
AU - Zwart, Rob
AU - Postma, Alex V
AU - Meijers-Heijboer, Hanne E J
AU - Moorselaar, R Jeroen A
AU - Wolthuis, Rob M F
AU - Houweling, Arjan C
N1 - Publisher Copyright: © The Author(s) 2022. Published by Oxford University Press.
PY - 2023/3/20
Y1 - 2023/3/20
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85150666801&partnerID=8YFLogxK
U2 - 10.1093/hmg/ddac288
DO - 10.1093/hmg/ddac288
M3 - Article
C2 - 36440963
VL - 32
SP - 1223
EP - 1235
JO - Human molecular genetics
JF - Human molecular genetics
SN - 0964-6906
IS - 7
ER -
ID: 30633605