{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T07:34:36Z","timestamp":1790494476940,"version":"4.1.0"},"reference-count":23,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2013,10,29]],"date-time":"2013-10-29T00:00:00Z","timestamp":1383004800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American J of Med Genetics Pt A"],"published-print":{"date-parts":[[2014,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:label\/><jats:p>Severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN) is an extremely rare severe skeletal dysplasia characterized by significant developmental delay, brain structural abnormalities, hearing loss, and acanthosis nigricans. The disorder is the result of a single missense mutation at codon 650 (p.Lys650Met) in the fibroblast growth factor receptor 3 gene (<jats:italic>FGFR3<\/jats:italic>). We describe a child who initially presented with a mild achondroplasia or hypochondroplasia like phenotype. Molecular analysis of the <jats:italic>FGFR3<\/jats:italic> gene showed the common SADDAN mutation and a second novel mutation at codon 651 (p.Thr651Pro). Both mutations were shown to occur on the same allele (<jats:italic>cis<\/jats:italic>) and de novo. Transient transfection studies with FGFR3 double mutant constructs show that the p.Thr651Pro mutation causes a dramatic decrease in constitutive receptor kinase activity than that observed by the p.Lys650Met mutation. Our data suggest that the molecular effect by the p.Thr651Pro is to elicit a conformational change that decreases the FGFR3 tyrosine kinase activity, which is constitutively activated by the SADDAN mutation. Due to the inheritance of both a gain\u2010of\u2010function and a loss\u2010of\u2010function mutation, we conclude that a reduction of constitutive activation caused the milder skeletal phenotype. Although the occurrence of double mutations are expected to be rare, the presence of other <jats:italic>FGFR3<\/jats:italic> modifiers may be responsible for some of the clinically discrepant skeletal dysplasia cases. \u00a9 2013 Wiley Periodicals, Inc.<\/jats:p><\/jats:sec>","DOI":"10.1002\/ajmg.a.36236","type":"journal-article","created":{"date-parts":[[2013,10,29]],"date-time":"2013-10-29T17:27:17Z","timestamp":1383067637000},"page":"243-250","source":"Crossref","is-referenced-by-count":5,"title":["Suppression of severe achondroplasia with developmental delay and acanthosis nigricans by the p.Thr651Pro mutation"],"prefix":"10.1002","volume":"164","author":[{"given":"Kandamurugu","family":"Manickam","sequence":"first","affiliation":[{"name":"Section of Human and Molecular Genetics Nationwide Children's Hospital Columbus Ohio"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel J.","family":"Donoghue","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry Moores UCSD Cancer Center University of California San Diego La Jolla California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"April N.","family":"Meyer","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry Moores UCSD Cancer Center University of California San Diego La Jolla California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pamela J.","family":"Snyder","sequence":"additional","affiliation":[{"name":"Department of Pathology The Ohio State University Columbus Ohio"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas W.","family":"Prior","sequence":"additional","affiliation":[{"name":"Department of Pathology The Ohio State University Columbus 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