mutations associate with a broad spectrum of inner ear and craniofacial phenotypes that show inter- and intrafamilial variability. Our study confirms that at least some recessive mutations of FGF3
may not always result in fully penetrant LAMM syndrome. Furthermore, we noted a less prominent dental phenotype in subjects with p.R95W, in contrast to the severe dental phenotype reported from the Somali family [16
]. Taken together, our results show that the manifestations of recessive FGF3
mutations can involve nearly non-syndromic deafness with variable inner ear structural development. In this regard, mutations of either LRTOMT
] or FGF3
should be considered when incompletely characterized nonsyndromic deafness is found to be linked to genetic markers of the DFNB63
locus on chromosome 11q 13.2 -q13.3.
The less severe phenotype associated with p.R95W segregating in Pakistani family PKDF817 is probably not due solely to genetic background, since the milder phenotype of homozygous p.R95W individuals has also been reported in an unrelated family from Somalia. The amino acid substitution of p.R95W may have a milder pathogenic effect as compared with other mutations of FGF. Our molecular modeling results support the possibility of less severe pathogenic effects of this allele since this variant is predicted to affect neither FGFR2b receptor nor heparan sulfate binding sites. Alone or in combination with a less severe pathogenic potential of p.R95W, there might be a differential effect of mutant alleles of FGF3 on different target organs. While these molecular models provide a plausible rationale for the effects of the mutations identified here, there remains the caveat that available structural information does not account for the role that receptor glycosylation might play in FGF interaction. In addition, phenotypic variability within and between the affected individuals in these two families also indicates a role for environment, stochastic events, genetic background, or a combination of these influences. In affected members of family PKDF817, we could not find a variant in FGF10, a potential candidate for a modifier of FGF3. To address the presence of modifiers, if any, larger families segregating a milder phenotype and p.R95W would be required for linkage analyses.
Our identification of a mild to moderate conductive hearing loss in heterozygous carriers raises the question of whether p.R95W exerts a semi-dominant pathogenic effect upon the function of FGF3. These data warrant careful interpretation, since we were unable to obtain information about the status of the tympanic membrane and ossicles in carriers. We initially reasoned that this may reflect the same pathogenic mechanism underlying autosomal dominant lacrimo-auriculo-dento-digital syndrome (LADD syndrome; OMIM 149730) caused by heterozygous mutations of FGFR2b
]. FGF3 is known to bind to FGFR2b with high affinity [34
]. Some patients with LADD syndrome have been reported to show isolated mild conductive hearing loss [36
], although many patients manifest a mild to moderate mixed type hearing loss. Moreover, the dental and auricular phenotypes from LADD syndrome patients are very similar with those in LAMM syndrome, while another autosomal dominant oto-dental syndrome (MIM 166750) recently reported in association with heterozygous microdeletions affecting FGF3
] shows significantly different dental phenotypes. In this regard, this possible semi-dominant phenotype might be consistent with the hypothesis that p.R95W affects the interaction between FGF3 and FGFR2 [16
]. However, our molecular modeling results argue against this hypothesis, since p.R95 is located away from the FGFR2b binding surfaces of FGF3. Alternatively, an allele of a totally different gene accounts for the hearing loss in p.R95W heterozygous carriers in the inbred family PKDF817, as the Somali p.R95W heterozygotes were reported not to have hearing loss [16
] The resolution of this question will require careful molecular and clinical examination of additional carriers of this allele and other mutations of FGF3
. The inner ear phenotypic variability within families is consistent with the highly variable inner ear phenotype of Fgf3
knockout mice on a uniform genetic background [18
] and functional redundancy of Fgf3
in otic vesicle formation [17
The options for auditory rehabilitation of LAMM patients with CLA are limited to vibrotactile hearing devices or brainstem implants. The presence of an osseous IAC and a cochleovestibular nerve has never been described in association with homozygous FGF3 mutations before this study. The presence of a cochleovestibular nerve and a cochlear remnant is a significant consideration for cochlear implantation candidacy. Because of intrafamilial variability, some patients with FGF3-related hearing loss are potential candidates for cochlear implantation, even if CLA has already been documented in other affected family members.