Alternative titles; symbols
Other entities represented in this entry:
HGNC Approved Gene Symbol: FGF3
SNOMEDCT: 702360007;
Cytogenetic location: 11q13.3 Genomic coordinates (GRCh38) : 11:69,809,968-69,819,416 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11q13.3 | Deafness, congenital with inner ear agenesis, microtia, and microdontia | 610706 | Autosomal recessive | 3 |
FGF3 is involved in inner ear development (Represa et al., 1991; Tekin et al., 2007).
Like Int1 (see 164820), Int2 is an oncogene implicated in mouse mammary carcinoma. By low-stringency hybridization, Casey et al. (1986) found homologous genes in a variety of mammalian species, including humans, but not in other classes or phyla. In 9 primary human breast tumors, 3 breast tumor cell lines, and 3 normal persons, no evidence of gross amplification or rearrangement of the INT2 locus was found. Three RFLPs were observed.
Brookes et al. (1989) determined that the predicted 239-amino acid INT2 protein is 89% identical to mouse Int2 over the first 217 residues, but the C terminus is completely divergent.
Brookes et al. (1989) reported that the INT2 gene contains 3 exons which correspond to those in mouse Int2.
By a combination of in situ and somatic cell hybridization, Casey et al. (1986) mapped the INT2 gene to 11q13.
As pointed out by Nusse et al. (1991), the INT1, INT2, and INT3 (164951) genes are fundamentally unrelated. They were given similar designations because they shared in common the fact that they were activated in some mammary tumors by integration of MMTV proviruses. The INT2 gene encodes a member of the fibroblast growth factor (FGF) family (Dickson and Peters, 1987). Thus, the similarity in name between INT1 (on 12q) and INT2 (on 11q) cannot be taken as further evidence of homeology of chromosomes 11 and 12. The existence of fibroblast growth factor-6 (134921) on 12p13 may reflect homeology.
Fibroblast growth factors have been associated with mesoderm induction in the amphibian embryo, and INT2 has a distinct pattern of expression throughout development in vertebrates. In the mouse embryo, Int2 transcripts were detected in the rhombencephalon at a developmental stage when the induction of the inner ear occurs. Represa et al. (1991) provided direct evidence that Int2 constitutes a signal for the induction of the otic vesicle, the primordium of the inner ear: the formation of the otic vesicle was inhibited by antisense oligonucleotides targeted to the secreted form of Int2, and by antibodies against Int2 oncoproteins; and basic FGF can mimic the inductive signal in the absence of the rhombencephalon. Congenital deafness due to mutation in the INT2 gene could be sought by identifying a form of deafness that maps to 11q. Examples of oncogenes or tumor suppressor genes that are known also to be 'teratogenes' include WT1 (607102), KIT (164920), GLI3 (165240), PAX3 (606597), and RET (164761).
Using immunohistochemistry with a tissue microarray containing 406 nonsmall cell lung cancer (see NSCLC; 211980) samples, Tai et al. (2006) documented overexpression of FGF3 and EGFR (131550) in 61% and 69% of samples, respectively. They found significant correlation (p less than 0.001) between overexpression of EGFR and of FGF3. Tai et al. (2006) suggested that co-overexpression of EGFR and FGF3 may play an important role in the pathogenesis of lung carcinoma.
Reviews
In their review, Frenz et al. (2010) noted that there is a critical period when development of the inner ear is dependent upon signaling through retinoic acid and its receptors (see 180240). They presented a model whereby either over- or underavailability of retinoic acid disrupts FGF3 and FGF10 (602115) activation, leading to altered expression of the downstream target genes DLX5 (600028) and DLX6 (600030) and defects in inner ear development.
Tekin et al. (2007) identified 9 individuals from 3 unrelated Turkish families with a novel autosomal recessive syndrome characterized by type I microtia, microdontia, and profound congenital deafness associated with complete absence of inner ear structures (Michel aplasia) (610706). Using a microarray method for genomewide linkage analysis searching for homozygous SNP blocks that were shared by all affected members, a region on 11q13 came into consideration. All 5 affected individuals in 1 family were homozygous for 9 consecutive SNPs in the region of 11q13 that contains the FGF3 gene. Because of overlap features of the syndrome in these patients to the LADD syndrome (149730), Tekin et al. (2007) considered that homozygous mutation in a fibroblast growth factor might be responsible. A homozygous missense mutation in FGF3, ser156 to pro (164950.0001), was found in 1 family; in the second family, a homozygous nonsense mutation, arg104 to ter (164950.0002), was found; and in the third family, a homozygous 1-bp deletion, 616delG (164950.0003), was found.
In affected members of a large consanguineous Saudi Arabian family with deafness, microtia, and microdontia, Alsmadi et al. (2009) identified a homozygous mutation in the FGF3 gene (164950.0004).
In 2 families with otodental dysplasia (166750) and 1 with otodental dysplasia and coloboma Gregory-Evans et al. (2007) identified overlapping hemizygous microdeletions on chromosome 11q13, the smallest of which spanned 43 kb from rs9666584 in the 5-prime untranslated region of the FGF4 gene (164980) to rs41408348 in the 5-prime untranslated region of the FGF3 gene. In the family with otodental dysplasia and coloboma, the microdeletion spanned 490 kb and encompassed the FADD gene (602457). Gregory-Evans et al. (2007) suggested that FGF3 haploinsufficiency is likely the cause of otodental syndrome and that FADD haploinsufficiency accounts for the associated ocular coloboma.
Sensi et al. (2011) reported 2 families with deafness, microtia, and microdontia, 1 from Albania and 1 from Italy, in which affected individuals were compound heterozygous for mutations in the FGF3 gene (164950.0002 and 164950.0007-164950.0009), respectively. The authors stated that these were the first compound heterozygotes for mutations in the FGF3 gene to be reported.
Martinez-Morales et al. (2005) demonstrated that Fgf3 and Fgf8 (600483) cooperate in initiating neuronal differentiation in the zebrafish retina.
Dogs with a characteristic dorsal hair ridge seem to have been present in both Africa and Asia long before European colonization. The Rhodesian ridgeback dog, first registered in South Africa in 1924, is most likely a blend of European dogs (brought to Africa by early colonizers) and an extinct indigenous breed of Africa. There are Thai and Vietnamese dogs with a dorsal hair ridge closely resembling the one found in Rhodesian ridgeback dogs. Salmon Hillbertz et al. (2007) performed histology of the skin from a ridged dog, which showed lateral orientation of the hair follicles and sebaceous glands; in contrast, skin from ridgeless dogs showed caudally oriented hair follicles. Ridgeback dogs are affected by the congenital malformation dermoid sinus, which closely resembles a neural tube defect in humans usually called dermal sinus (see 600145). Salmon Hillbertz et al. (2007) showed that the causative mutation in ridgeback dogs is a 133-kb duplication involving 3 fibroblast growth factor genes: FGF3, FGF4 (164980), and FGF19 (603891), as well as ORAOV1 (607224) and the 3-prime end of the CCND1 gene (168461). All of these genes are syntenic in the human on the long arm of chromosome 11; they are located on chromosome 18 of the dog. In these studies, Salmon Hillbertz et al. (2007) assumed a genetic model in which (i) ridgeless dogs are homozygous (r/r) for the wildtype allele, (ii) ridged dogs without dermoid sinus are heterozygous or homozygous for the Ridge allele (R/r or R/R), and (iii) ridged dogs with dermoid sinus are homozygous R/R. Neither ridgeless dogs or those with dermoid sinus are allowed for breeding by the Rhodesian ridgeback clubs. This leads to overdominance, because the heterozygote is the favored genotype: it expresses the ridge and has a low incidence of dermoid sinus. The problem with dermoid sinus could be virtually eliminated by allowing ridgeless dogs in breeding and by avoiding mating between ridged dogs.
In zebrafish, mechanosensory organs called neuromasts are deposited at regular intervals by the migrating posterior lateral line (pLL) primordium. The pLL primordium is organized into polarized rosettes representing protoneuromasts, each with a central atoh1a-positive focus of mechanosensory precursors. Nechiporuk and Raible (2008) showed that rosettes form cyclically from a progenitor pool at the leading zone of the primordium as neuromasts are deposited from the trailing region. Fgf3 and Fgf10 (602115) signals localized to the leading zone are required for rosette formation, atoh1a expression, and primordium migration. Nechiporuk and Raible (2008) proposed that the fibroblast growth factor source controls primordium organization, which, in turn, regulates the periodicity of neuromast deposition.
In a consanguineous Turkish family with 5 affected individuals in 3 sibships, Tekin et al. (2007) demonstrated that an autosomal syndrome characterized by type I microtia, microdontia, and profound congenital deafness associated with complete absence of inner ear structures (Michel aplasia) (610706) was caused by a missense mutation in the FGF3 gene: 466T-C (S156P).
In a consanguineous Turkish family, Tekin et al. (2007) found that a form of syndromic deafness characterized by inner ear agenesis, microtia, and microdontia (610706) was caused by a homozygous 310C-T transition in the FGF3 gene, resulting in an arg104-to-ter (R104X) substitution.
In a 4-year-old Italian girl with microtia, microdontia, and sensorineural hearing loss, Sensi et al. (2011) identified compound heterozygosity for R104X and a tyr49-to-cys (Y49C; 164950.0007) substitution at a highly conserved residue in the FGF3 gene. Her unaffected mother, who was heterozygous for the R104X mutation, had a history of ear surgery for a defect said to be similar to that of her affected daughter (no photographs were available).
In a Turkish family, Tekin et al. (2007) described a single case of syndromic deafness characterized by inner ear agenesis, microtia, and microdontia (610706). The authors identified a 1-bp deletion in the FGF3 gene: 616delG. The mutation causes a frameshift starting from codon 206 resulting in the production of a completely altered protein that terminates after 116 codons (Val206SfsTer117).
In 21 affected individuals from a large consanguineous Saudi Arabian family with autosomal recessive deafness, microtia, and microdontia (610706), Alsmadi et al. (2009) identified a homozygous 196G-T transversion in the FGF3 gene, resulting in a gly66-to-cys (G66C) substitution in a highly conserved residue.
In 3 affected sibs of a consanguineous Turkish family with autosomal recessive deafness, microtia, and microdontia (610706), Tekin et al. (2008) identified a homozygous 17T-C transition in the FGF3 gene, resulting in a leu6-to-pro (L6P) substitution within the signal site and predicted to impair protein secretion. The mutation was not found in 200 controls.
In a Turkish girl, born of first-cousin parents, with autosomal recessive deafness, microtia, and microdontia (610706), Tekin et al. (2008) identified a homozygous 1-bp deletion (254delT) in exon 2 of the FGF3 gene, predicted to result in premature termination (Ile85MetfsTer15). The mutation was not found in 200 controls.
For discussion of the tyr49-to-cys (Y49C) mutation in the FGF3 gene that was found in compound heterozygous state in a patient with microtia, microdontia, and sensorineural hearing loss (610706) by Sensi et al. (2011), see 164950.0002.
In an Albanian brother and sister, aged 12 and 9 years, respectively, with microtia, microdontia, and sensorineural hearing loss (610706), Sensi et al. (2011) identified compound heterozygosity for mutations in the FGF3 gene: a 317A-G transition in exon 2, resulting in a tyr106-to-cys (Y106C) substitution at a highly conserved residue, and a 2-bp deletion (457_458delTG; 164950.0009) in exon 3, resulting in a frameshift that was predicted to cause a premature termination codon (Trp153ValfsTer51). The unaffected parents were each heterozygous for 1 of the mutations; neither mutation was found in 50 controls of the same European background. CT scan of the petrous bones revealed bilateral involvement of middle ear as well as inner ear structures in both sibs.
For discussion of the 2-bp deletion in the FGF3 gene (457_458delTG) that was found in compound heterozygous state in sibs with microtia, microdontia, and sensorineural hearing loss (610706) by Sensi et al. (2011), see 164950.0008.
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Sensi, A., Ceruti, S., Trevisi, P., Gualandi, F., Busi, M., Donati, I., Neri, M., Ferlini, A., Martini, A. LAMM syndrome with middle ear dysplasia associated with compound heterozygosity for FGF3 mutations. Am. J. Med. Genet. 155A: 1096-1101, 2011. [PubMed: 21480479] [Full Text: https://doi.org/10.1002/ajmg.a.33962]
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