title: A FGF3 mutation associated with differential inner ear malformation, microtia, and microdontia.
abstract: OBJECTIVE
  Analysis of association between genotype and phenotype.
  
  
  METHODS
  Prospective genetic study in a family.
  
  
  METHODS
  Auditory investigations, computer tomography, and genetic sequencing of the fibroblast growth factor 3 (FGF3) gene were performed on a Somali family presenting with autosomal recessive, hearing impairment, microdontia, and outer ear morphologies ranging from normal auricle development to microtia assessed as type 1 Weerda dysplasia in affected individuals.
  
  
  RESULTS
  Computed tomography imaging identified differential inter- and intraindividual malformations of the inner ear including labyrinth aplasia, development of a common cavity to the presence of a cochlear with 1.5 windings (Mondini malformation) in affected individuals, symptoms similar to those described as labyrinth aplasia, microtia, and microdontia (LAMM) syndrome, caused by mutations in FGF3. Genetic sequencing revealed the presence of a novel p.R95W missense mutation in FGF3 segregating with pathology. The p.R95W mutation substitutes a positively charged arginine for a polar tryptophan in the highly conserved RYLAM consensus of the beta 6 sheet of FGF3 that interacts with FGFR2.
  
  
  CONCLUSIONS
  These findings describe, for the first time, variable inner ear malformations and outer ear dysplasia in the presence of constant microdontia, associated with homozygous inheritance of the p.R95W mutation in FGF3, mirroring phenotypes observed in mouse models ablating FGF3/FGFR2 signaling.
authors: Department of Otorhinolaryngology, Division of Molecular Pharmacokinetics and Imaging, Biochemical Genetics and National Neonatal Screening Laboratories, Vienna, Austria.
authors: Reinhard
authors: R
authors: Ramsebner
authors: Martin
authors: M
authors: Ludwig
authors: Thomas
authors: T
authors: Parzefall
authors: Trevor
authors: T
authors: Lucas
authors: Wolf-Dieter
authors: WD
authors: Baumgartner
authors: Olaf
authors: O
authors: Bodamer
authors: Filiz Basak
authors: FB
authors: Cengiz
authors: Christian
authors: C
authors: Schoefer
authors: Mustafa
authors: M
authors: Tekin
authors: Klemens
authors: K
authors: Frei
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D004431:Ear, External / Q000002:abnormalities*; D007758:Ear, Inner / Q000002:abnormalities*; D005260:Female; D051518:Fibroblast Growth Factor 3 / Q000235:genetics*; D006319:Hearing Loss, Sensorineural / Q000151:congenital / Q000235:genetics; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D010375:Pedigree; D014071:Tooth Abnormalities / Q000235:genetics*
chemical_list: D051518:Fibroblast Growth Factor 3