PPM1K was first reported in relation to autosomal recessive maple syrup urine disease, mild variant in 2013 (Oyarzabal A, et al., 2013, PMID: 23086801). Two cases have been identified in two publications (PMIDs: 23242558, 36706222) with homozygous putative loss of function variants (frameshift and start-loss). In addition to the two cases, evidence supporting this gene-disease relationship includes the experimental data of the role of PPM1K as the BCKD complex E1α phosphatase (PMID: 19411760), its interaction with additional MSUD genes BCKDHA and DBT (PMID: 19411760), its alteration of dephosphorylation in both patient and non-patient cells which could be rescued with WT expression (PMID: 23086801 and PMID: 19411760), a knockdown zebrafish model (PMID: 17374715) with limited relevant characterization, and a knockout mouse (PMID: 19411760 ) which recapitulated the characteristic elevation of branched chain amino acids seen in patients. In summary, there is moderate genetic evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged.
This gene-disease pair was originally approved by the Aminoacidopathy GCEP on 09/25/2020. It was reevaluated on 10/25/2023. As a result of this reevaluation a second case was identified (PMID: 36706222) and increased the classification from Limited to Moderate (SOP Version 9).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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