Submission Details

Hereditary Paraganglioma-Pheochromocytoma Syndromes (PGL/PCC) [MONDO:0017366, PMID: 20301715] describes susceptibility to pheochromocytoma and paraganglioma with autosomal dominant inheritance. The MAX gene [MIM# 154950] -MYC associated factor X- is one of the susceptibility genes resulting in genetic predisposition to PCC, mostly in patients without familial antecedents, probably due to a paternal transmission effect [PMID 21685915 and 22452945]. MAX was first reported in relation to PGL/PCC in 2011 [Comino-Méndez I et al., PMID: 21685915]. Genetic evidence includes loss of function and missense variants in MAX found in Hereditary PCC with missense variants likely being the dominant negative effect [PMID: 26070438]. Genetic evidence was scored for loss of function variants [PMID 21685915, 22452945 and 28384794]. Missense variants and deletions are also reported but not used for this curation [PMID: 26670126 and 23666964]. Experimental evidence demonstrated loss MAX gene expression and loss of heterozygosity (LOH) in patient tumors carrying LoF variants [PMID: 21685915]. Loss of functional MAX expression in a Rat Pheochromocytoma (PCC) cell line (PC12) and reduction of cell proliferation by reintroducing MAX expression [PMID: 7791753], which showed MAX is a tumor suppressor gene. Luciferase reporter activity assays with 9 missense variants confirmed the dominant negative mechanism in pathogenesis of hereditary PCC [PMID: 26070438]. The encoded MAX protein is the most conserved dimerization component of the MYC-MAX-MXD1 network of basic helix-loop-helix leucine zipper (bHLHZ) transcription factors that regulate cell proliferation, differentiation, and apoptosis. MAX is definitely associated with autosomal dominant HPGL/PCC syndrome, most commonly pheochromocytoma. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.