HTRA2 was first reported in relation to autosomal recessive 3-methylglutaconic aciduria type 8 in 2016 (Mandel H, et al., 2016, PMID: 27208207). HTRA2 encodes an ATP-independent serine protease that resides in the mitochondrial intermembrane space, but upon cellular stress, HTRA2 is processed to a shorter form and released into the cytosol. Here, it facilitates cell death through cleavage of apoptosis inhibitor proteins. Mutations in the gene lead to increased susceptibility to apoptosis and neurodegeneration. The clinical features include hypotonia, dystonia, seizures and cardio-respiratory difficulties. Urine analysis characteristically shows excretion of 3-methylglutaconic acid. Eight variants (missense, indel, frameshift, and splice variants) have been reported in 7 probands (and 3 family members) from 4 publications (PMIDs: 27208207, 27696117, 30114719, and 32445293). This gene-disease association is also supported by its biochemical functions in proteolytic cleavage and apoptosis (PMID: 11604410), which are altered in patient cells (PMIDs: 27696117. 27208207). As well two mouse models that recapitulate to the human phenotype (PMIDs: 15509788, 14534547). In summary, HTRA2 is definitively associated with autosomal recessive 3-methylglutaconic aciduria type 8.
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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