Paraganglioma_phaeochromocytoma
Gene: DLST
PMID: 30929736
4 unrelated patients with pheochromocytomas and paragangliomas with the same germline heterozygous missense variant in DLST gene (G374E). Analysis of tumour tissue available from 3 of the patients showed loss of heterozygosity (LOH) for DLST due to uniparental disomy (UPD) of the paternal chromosome. None of the patients had a family history of the disorder, although 3 probands had asymptomatic family members who carried the mutation, consistent with incomplete penetrance. Knockdown of the DLST gene in human H838 cells resulted in a significant block in carbon flow in the tricarboxylic acid (TCA) cycle, which was rescued by wildtype DLST, but not by the G374E mutant. Many PPGL genes encode proteins involved in the tricarboxylic acid (TCA) cycle. In vitro functional expression studies showed that the G374E mutant had compromised catalytic activity compared to wildtype, resulting in a high alpha-KG/fumarate ratio and accumulation of the oncometabolite 2-hydroxyglutaric acid (2HG), particularly the L-2HG enantiomer. Analysis of patient tumours showed strong immunostaining for DLST as well as a hypermethylated phenotype, categorized in the non-CIMP (CpG island methylator phenotype) cluster, and a pseudohypoxic state with increased expression of HIF3A. The findings indicated that DLST can act as a tumour suppression gene. Heterozygous missense variants in DLST (R231Q, D304N, and Y422C) were found in 3 additional probands, but in vitro functional studies of these 3 other missense variants indicated that they behaved similar to wildtype DLST in the assay used. None of the patients besides those with the G374E variant showed LOH in tumour tissue.
PMID: 30929736
2 unrelated patients with pheochromocytomas and paragangliomas with 2 different germline heterozygous missense variants in DLST gene (Pro384Leu, Gly374Glu). Tumour testing in 1 patient identified a second somatic missense variant in DLST (Thr383Ala). They showed the p.(Pro384Leu) variant, located in the catalytic site of DLST, leads to a dramatic but not complete loss of catalytic activity.
Sources: Expert list, Expert Review, LiteratureCreated: 18 Sep 2024, 9:27 p.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
Paragangliomas 7, MONDO:0032771; Pheochromocytoma, MONDO:0008233; Hereditary pheochromocytoma-paraganglioma, MONDO:0017366; Pheochromocytoma/paraganglioma syndrome 7, MIM#618475
Publications
Gene: dlst has been classified as Red List (Low Evidence).
gene: DLST was added gene: DLST was added to Paraganglioma_phaeochromocytoma. Sources: Expert list,Expert Review,Literature Mode of inheritance for gene: DLST was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: DLST were set to PMID: 30929736, 33180916 Phenotypes for gene: DLST were set to Paragangliomas 7, MONDO:0032771; Pheochromocytoma, MONDO:0008233; Hereditary pheochromocytoma-paraganglioma, MONDO:0017366; Pheochromocytoma/paraganglioma syndrome 7, MIM#618475 Review for gene: DLST was set to RED