DNAJC12 was first reported in relation to autosomal recessive hyperphenylalaninemia (HPA) in 2017 (Anikster Y, et al., 2017, PMID: 28132689). The co-chaperone DNAJC12 is, together with the 70 kDa heat shock protein (HSP70), thought to be responsible for the proper folding of phenylalanine hydroxylase (PAH), leading to HPA in patients (reviewed in PMID: 29174366). At least 11 unique variants (e.g. missense, nonsense, frameshift, and large deletion) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Biallelic missense variants in this gene have been reported in at least 7 probands in 5 publications (PMIDs: 28132689, 30179615, 28892570, 28794131, 30139987). Variants in this gene segregated with disease in 5 additional family members. More evidence is available in the literature, but the maximum score for genetic evidence has been reached. This gene-disease relationship is supported by the protein interactions that occur between DNAJC12 and PAH, TH, and TPH2 which are consistent with the biochemical abnormalities observed in patients and the functional alteration observed in patient cells with reduced PAH enzymatic activity (PMID: 28132689). In summary, DNAJC12 is definitively associated with autosomal recessive hyperphenylalaninemia.
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