A FGF3 mutation associated with differential inner ear malformation, microtia, and microdontia.
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.
Ramsebner
Reinhard
R
Department of Otorhinolaryngology, Division of Molecular Pharmacokinetics and Imaging, Biochemical Genetics and National Neonatal Screening Laboratories, Vienna, Austria.
Ludwig
Martin
M
Parzefall
Thomas
T
Lucas
Trevor
T
Baumgartner
Wolf-Dieter
WD
Bodamer
Olaf
O
Cengiz
Filiz Basak
FB
Schoefer
Christian
C
Tekin
Mustafa
M
Frei
Klemens
K
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*
D051518:Fibroblast Growth Factor 3