PMC:4570552 / 1743-4278 JSONTXT

{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/4570552","sourcedb":"PMC","sourceid":"4570552","source_url":"https://www.ncbi.nlm.nih.gov/pmc/4570552","text":"Dual sensory impairment due to cataracts and sensorineural hearing loss is a well-recognized consequence of infectious teratogenic exposure (i.e., fetal rubella syndrome), but only rarely observed as a developmental defect in genetic disease phenotypes. In 1996, Gripp and co-workers described two unrelated subjects with congenital cataracts and sensorineural deafness associated with intellectual disability, short stature, brachycephaly, and a distinctive flat facial appearance and considered this trait to represent a previously unrecognized syndrome (MIM 601088).1 In their clinical report,2 Aymé and Philip discussed on the similarities between the clinical features exhibited by their case and others previously reported by other authors4 and those of the patients reported by Gripp and co-authors.1 Aymè and Philip concluded that all these cases were clinically related to the patient originally described by Fine and Lubinsky.3 For this reason, the authors proposed the term “Fine-Lubinsky syndrome” to define this developmental disorder. Since then, a few additional cases exhibiting features fitting or partially overlapping this condition(s) have been reported,5–9 and whether these phenotypes represent variable manifestations of a single nosologic entity remained unresolved. Autosomal recessive inheritance was suggested, based on affected siblings.7 Here, whole-exome sequencing (WES) on a single affected individual and Sanger sequencing on a selected cohort of subjects with phenotype suggestive of FLS were used to identify a narrow spectrum of missense mutations in v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog (MAF [MIM 177075]) as the molecular cause underlying this previously poorly understood multisystem disorder, and delineate its clinical phenotype. The provided biochemical and functional data demonstrate that the mutations identified in this study specifically affect the phosphorylation of MAF promoted by the protein GSK3, which is a serine/threonine kinase that requires a specific recognition motif for its action—i.e., the presence of a proline residue adjacent to the serine/threonine residue that is substrate of its action. The impaired phosphorylation at those sites affects MAF ubiquitination, which, in turn, impairs degradation of the mutated (unphosphorylated and unubiquitinilated) protein, generally mediated by the proteasome complex. Finally, these mutations are able to induce neurodevelopmental defects in vivo (zebrafish), thus representing dominant-acting mutations.","tracks":[{"project":"2_test","denotations":[{"id":"25865493-8834052-2043999","span":{"begin":569,"end":570},"obj":"8834052"},{"id":"25865493-8867660-2044000","span":{"begin":596,"end":597},"obj":"8867660"},{"id":"25865493-9188678-2044001","span":{"begin":745,"end":746},"obj":"9188678"},{"id":"25865493-8834052-2044002","span":{"begin":806,"end":807},"obj":"8834052"},{"id":"25865493-6432966-2044003","span":{"begin":936,"end":937},"obj":"6432966"},{"id":"25865493-17935251-2044004","span":{"begin":1176,"end":1177},"obj":"17935251"},{"id":"25865493-12072800-2044004","span":{"begin":1176,"end":1177},"obj":"12072800"},{"id":"25865493-17394214-2044004","span":{"begin":1176,"end":1177},"obj":"17394214"},{"id":"25865493-18417983-2044004","span":{"begin":1176,"end":1177},"obj":"18417983"},{"id":"25865493-19396831-2044004","span":{"begin":1176,"end":1177},"obj":"19396831"},{"id":"25865493-17394214-2044005","span":{"begin":1365,"end":1366},"obj":"17394214"}],"attributes":[{"subj":"25865493-8834052-2043999","pred":"source","obj":"2_test"},{"subj":"25865493-8867660-2044000","pred":"source","obj":"2_test"},{"subj":"25865493-9188678-2044001","pred":"source","obj":"2_test"},{"subj":"25865493-8834052-2044002","pred":"source","obj":"2_test"},{"subj":"25865493-6432966-2044003","pred":"source","obj":"2_test"},{"subj":"25865493-17935251-2044004","pred":"source","obj":"2_test"},{"subj":"25865493-12072800-2044004","pred":"source","obj":"2_test"},{"subj":"25865493-17394214-2044004","pred":"source","obj":"2_test"},{"subj":"25865493-18417983-2044004","pred":"source","obj":"2_test"},{"subj":"25865493-19396831-2044004","pred":"source","obj":"2_test"},{"subj":"25865493-17394214-2044005","pred":"source","obj":"2_test"}]}],"config":{"attribute types":[{"pred":"source","value type":"selection","values":[{"id":"2_test","color":"#93ec95","default":true}]}]}}