PMC:4375449 / 10949-12518
Annnotations
{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/4375449","sourcedb":"PMC","sourceid":"4375449","source_url":"https://www.ncbi.nlm.nih.gov/pmc/4375449","text":"The different phenotypes so far associated with mutations in PNKP do not seem to relate to either the type or the location of the mutation (Figure 1). PNKP is a modular protein with three domains: an amino-terminal fork-head-associated (FHA) domain, which mediates interactions with the scaffold proteins XRCC1 and XRCC4; a DNA phosphatase domain; and a DNA kinase domain.18 The same homozygous variant, p.Thr424Glyfs∗49 (c.1253_1269dup), located in the kinase domain of the protein, has been found in individuals with progressive cerebellar atrophy and in individuals with MCSZ (an autosomal-recessive syndrome characterized by microcephaly, early onset, intractable seizures, and developmental delay).13,14 We have now identified this same variant in compound heterozygosity with p.Gly375Trp in family 1. Missense substitutions in the FHA and phosphatase domains of the protein have only been associated with developmental syndromes. In most affected individuals, MCSZ was found to be caused by the p.Glu326Lys (c.1123G\u003eT) variant in homozygosity.13 In the present study, variants found to be associated with AOA were all located in, or adjacent to, the kinase region of the protein. The position of the most frequent variant, p.Gly375Trp, in this cohort is highly conserved across species (Figure S2) and is located in a potential ATP nucleotide-binding domain (amino acids 372–379) within the kinase region. Additionally, several in-silico-prediction software programs rate this variant as deleterious (SIFT score = 0; PolyPhen score = 0.999; CADD_phred = 18.51).19","tracks":[{"project":"2_test","denotations":[{"id":"25728773-15749016-2048973","span":{"begin":372,"end":374},"obj":"15749016"},{"id":"25728773-20118933-2048974","span":{"begin":706,"end":708},"obj":"20118933"},{"id":"25728773-23224214-2048974","span":{"begin":706,"end":708},"obj":"23224214"},{"id":"25728773-20118933-2048975","span":{"begin":1049,"end":1051},"obj":"20118933"},{"id":"25728773-23843252-2048976","span":{"begin":1567,"end":1569},"obj":"23843252"}],"attributes":[{"subj":"25728773-15749016-2048973","pred":"source","obj":"2_test"},{"subj":"25728773-20118933-2048974","pred":"source","obj":"2_test"},{"subj":"25728773-23224214-2048974","pred":"source","obj":"2_test"},{"subj":"25728773-20118933-2048975","pred":"source","obj":"2_test"},{"subj":"25728773-23843252-2048976","pred":"source","obj":"2_test"}]}],"config":{"attribute types":[{"pred":"source","value type":"selection","values":[{"id":"2_test","color":"#b6ec93","default":true}]}]}}