Homozygous FGF3 mutations result in congenital deafness with inner ear agenesis, microtia, and microdontia

Division of Clinical Molecular Pathology and Genetics, Department of Pediatrics, Ankara University School of Medicine, Ankara, Turkey.
Clinical Genetics (Impact Factor: 3.93). 06/2008; 73(6):554-65. DOI: 10.1111/j.1399-0004.2008.01004.x
Source: PubMed


Homozygous mutations in the fibroblast growth factor 3 (FGF3) gene have recently been discovered in an autosomal recessive form of syndromic deafness characterized by complete labyrinthine aplasia (Michel aplasia), microtia, and microdontia (OMIM 610706 - LAMM). In order to better characterize the phenotypic spectrum associated with FGF3 mutations, we sequenced the FGF3 gene in 10 unrelated families in which probands had congenital deafness associated with various inner ear anomalies, including Michel aplasia, with or without tooth or external ear anomalies. FGF3 sequence changes were not found in eight unrelated probands with isolated inner ear anomalies or with a cochlear malformation along with auricle and tooth anomalies. We identified two new homozygous FGF3 mutations, p.Leu6Pro (c.17T>C) and p. Ile85MetfsX15 (c.254delT), in four subjects from two unrelated families with LAMM. The p.Leu6Pro mutation occurred within the signal site of FGF3 and is predicted to impair its secretion. The c.254delT mutation results in truncation of FGF3. Both mutations completely co-segregated with the phenotype, and heterozygotes did not have any of the phenotypic findings of LAMM. Some affected children had large skin tags on the upper side of the auricles, which is a distinctive clinical component of the syndrome. Enlarged collateral emissary veins associated with stenosis of the jugular foramen were noted on computerized tomographies of most affected subjects with FGF3 mutations. However, similar venous anomalies were also detected in persons with non-syndromic Michel aplasia, suggesting that a direct causative role of impaired FGF3 signaling is unlikely.

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    • "Decreased in anterior cingulate in MDD (Evans et al., 2004) FGF3 Inner ear development (Frenz et al., 2010), works cooperatively with FGF8 in zebrafish retinal development (Martinez-Morales et al., 2005) Multiple mutations, likely loss of function Congenital deafness (Tekin et al., 2007, 2008; Alsmadi et al., 2009; Sensi et al., 2011) FGF7 Presynaptic organizing molecule for inhibitory synapses onto CA3 neurons (Umemori et al., 2004; Terauchi et al., 2010) Knockout FGF7-null mice are sensitive to PTZ kindling of seizures (Terauchi et al., 2010); enhanced mossy fiber sprouting and increased dentate gyrus neurogenesis (Lee et al., 2012) FGF10 Presynaptic organizing molecule (Umemori et al., 2004) FGF22 Presynaptic organizing molecule for excitatory synapses onto CA3 neurons (Umemori et al., 2004; Terauchi et al., 2010) Knockout FGF22-null mice are resistant to PTZ-induced kindling (Terauchi et al., 2010), do not have induction of DG neurogenesis or ectopic hilar cells with PTZ treatment despite having seizures (Lee and Umemori, 2013) "
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    • "Although limited to case reports, there is some human evidence that mutations in analogous genes regulated by retinoic acid in animals do produce hearing loss in humans. Homozygous Fgf3 mutations are associated with inner ear agenesis and accompanied sensorineural deafness [44] [45]. Interestingly none of the families in these reports had accompanying mutations in Fgf8 or Fgf10, indicating a difference between humans and mice since murine otic abnormalities require disruption of multiple fibroblast growth factor genes. "
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    • "FGF3 too is involved in placode formation [Itoh and Ornitz, 2008]; thus it is conceivable that middle ear involvement could actually be associated with FGF3 inactivation and not merely a coincidental finding. Tekin et al. [2008] looked for FGF3 mutations in eight subjects with inner ear abnormalities, without LAMM syndrome, and did not find any mutation [Tekin et al., 2008]. However, Ramsebner et al. [2010] found FGF3 mutations in a Somali family with a LAMM variant with different and variable inner ear abnormalities. "
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