Alternative titles; symbols
HGNC Approved Gene Symbol: EYA1
SNOMEDCT: 429448005;
Cytogenetic location: 8q13.3 Genomic coordinates (GRCh38): 8:71,197,433-71,548,094 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 8q13.3 | ?Otofaciocervical syndrome | 166780 | Autosomal dominant | 3 |
| Anterior segment anomalies with or without cataract | 602588 | Autosomal dominant | 3 | |
| Branchiootic syndrome 1 | 602588 | Autosomal dominant | 3 | |
| Branchiootorenal syndrome 1, with or without cataracts | 113650 | Autosomal dominant | 3 |
Members of the EYA family, including EYA1, have protein phosphatase function, and EYA enzymatic activity is required for regulating genes encoding growth control and signaling molecules, modulating precursor cell proliferation (summary by Li et al., 2003).
By positional cloning in the 8q13.3 region where the branchiootorenal dysplasia syndrome (BOR; 113650) maps, Abdelhak et al. (1997) identified a gene that they showed to be responsible for the disorder. The gene is a human homolog of the Drosophila 'eyes absent' gene (Eya) and was therefore called EYA1. The gene encodes a deduced 559-amino acid polypeptide with a predicted molecular mass of 61.2 kD. Abdelhak et al. (1997) also found a highly conserved 271-amino acid C-terminal region in the products of 2 other human genes, which were subsequently called EYA2 (601654) and EYA3 (601655), demonstrating the existence of a novel gene family.
Li et al. (2003) showed that EYA1 encodes a dual-function transcription factor with an N-terminal transcriptional coactivator region and a C-terminal dephosphorylation domain.
Abdelhak et al. (1997) studied the expression pattern of the mouse EYA1 ortholog and obtained results suggesting a role in the development of all components of the inner ear, from the emergence of the otic placode. In the developing kidney, the expression pattern indicated a role for Eya1 in the metanephric cells surrounding the 'just-divided' ureteric branches.
Xu et al. (1997) showed that in the limbs of 10.5-day mouse embryos, Eya1 expression was largely restricted to the flexor tendons, whereas Eya2 (601654) was expressed in the extensor tendons and probably also in the ligaments of the phalanges. They demonstrated that the proline/serine/threonine-rich N-terminal regions of the protein products of the Eya1, Eya2, and Eya3 (601655) genes have transcriptional activator activity. These results supported a role for the Eya genes in connective tissue patterning in the limbs.
Azuma et al. (2000) stated that in Drosophila, the Eya gene is involved in the formation of compound eyes. Flies with loss-of-function mutations of this gene develop no eyes and form ectopic eyes in the antennae and the ventral zone of the head on target expression. A highly conserved homologous gene in various invertebrates and vertebrates has been shown to function in the formation of the eye.
Using sequence analysis, Hsiao et al. (2001) identified 2 conserved mitogen-activated protein kinase (MAPK) sites in the EYA1 sequence. In vivo genetic analysis, together with in vitro kinase assay results, demonstrated that Eya is a substrate for extracellular signal-regulated kinase, the MAPK acting downstream in the receptor tyrosine kinase (RTK) signaling pathway. Hsiao et al. (2001) hypothesized that phosphorylation of Drosophila Eya provides a direct regulatory link between the RTK/Ras/MAPK signaling cascade and the retinal determination gene network. They concluded that Eya function in Drosophila is positively regulated by MAPK-mediated phosphorylation.
Buller et al. (2001) analyzed the functional importance of Eya domain missense mutations with respect to protein complex formation and cellular localization. Previously described point mutations did not alter protein localization; however, 3 mutations (glu330 to lys, 601653.0009; ser454 to pro, 601653.0012; and leu472 to arg, 601653.0013) disrupted interactions between Eya and the sine oculis homeobox protein (Six1; 601125) in both yeast and mammalian cells. Binding to Six2 (604994) was not impeded.
Rayapureddi et al. (2003) demonstrated that Eya is a protein-tyrosine phosphatase in Drosophila. It does not resemble the classical tyrosine phosphatases that use cysteine as a nucleophile and proceed by means of a thiol-phosphate intermediate. Rather, Eya is the prototype for a class of protein-tyrosine phosphatases that use a nucleophilic aspartic acid in a metal-dependent reaction. Furthermore, Rayapureddi et al. (2003) showed that the phosphatase activity of Eya contributes to its ability to induce eye formation in Drosophila.
Tootle et al. (2003) independently showed that Eya belongs to the phosphatase subgroup of the haloacid dehalogenase (HAD) superfamily, and proposed a function for it as a non-thiol-based protein-tyrosine phosphatase. Experiments performed in cultured Drosophila cells and in vitro indicated that Eya has intrinsic protein-tyrosine phosphatase activity and can autocatalytically dephosphorylate itself. Confirming the biologic significance of this function, mutations that disrupt the phosphatase active site severely compromise the ability of Eya to promote eye specification and development in Drosophila. Tootle et al. (2003) concluded that given the functional importance of phosphorylation-dependent modulation of transcription factor activity, this evidence for a nuclear transcriptional coactivator with intrinsic phosphatase activity suggests an unanticipated method of fine-tuning transcriptional regulation.
Grifone et al. (2004) found that among the Six and Eya gene products expressed in mouse skeletal muscle, Six1 and Eya1 accumulated preferentially in the nuclei of fast-twitch muscles. Forced coexpression of Six1 and Eya1 in the slow-twitch soleus muscle induced a transition to a fast-twitch fiber type, with activation of fast-twitch fiber-specific genes and a switch toward glycolytic metabolism.
Alkuraya et al. (2006) identified EYA1 as a substrate for sumoylation with SUMO1 (601912) in vivo. This was confirmed by abolishing the sumoylated Eya1 species with a SUMO-specific peptidase, SENP1. Furthermore, an Eya1 mutant protein in which 2 of 3 predicted high probability lysine residues were replaced with arginine displayed minimal sumoylation. In mice haploinsufficient for both Sumo1 and Eya1, the incidence of cleft lip/palate (36%) was significantly increased compared with that in mice haploinsufficient for Sumo1 (8.7%) or Eya1 (0.0%) alone.
Cook et al. (2009) reported that the protein-tyrosine phosphatase EYA is involved in promoting efficient DNA repair rather than apoptosis in response to genotoxic stress in mammalian embryonic kidney cells by executing a damage signal-dependent dephosphorylation of an H2AX (601772) carboxy-terminal tyrosine phosphate (Y142). This posttranslational modification determines the relative recruitment of either DNA repair or proapoptotic factors to the tail of serine-phosphorylated histone H2AX and allows it to function as an active determinant of repair/survival versus apoptotic responses to DNA damage, revealing an additional phosphorylation-dependent mechanism that modulates survival/apoptotic decisions during mammalian organogenesis.
Abdelhak et al. (1997) reported the complete genomic structure of the EYA1 gene. The gene consists of 16 coding exons and extends over 156 kb. It encodes various alternatively spliced transcripts differing only in their 5-prime regions.
Branchiootorenal Syndrome 1
To test for possible DNA rearrangements within EYA1 in BOR probands, Abdelhak et al. (1997) hybridized Southern blots containing DNA from 21 familial and sporadic patients with probes corresponding to exons A to G of the gene and the exon immediately adjacent to exon A (designated exon z). In a sporadic case of BOR, hybridization with exon D resulted in a signal of reduced intensity, suggesting a deletion; this reduction was not seen in the proband's parents. Hybridization with exons A and B resulted in signals of normal intensity, C resulted in a band shift, and E, F, and G resulted in bands of reduced intensity. It was estimated that the deletion in this individual spanned 5.8 to 7 kb. In another patient, Abdelhak et al. (1997) detected a premature stop codon in exon z (601653.0001); in a third patient, replacement of a T with CC insertion was detected in exon D (601653.0002). The affected family members of these 2 probands carried the same mutations, whereas the unaffected family members did not. In a fourth patient, a 1-bp insertion was detected in exon c. The phenotypically normal parent of this proband did not carry this mutation. In each of 4 other individuals, a mutation was detected.
Abdelhak et al. (1997) performed sequence analysis of the entire EYA1 coding region for 20 unrelated patients affected by BOR syndrome, and 6 novel mutations were identified. Sequence analysis of the coding region, including splice site junctions, as well as Southern blot analysis of the coding region and the 5-prime and 3-prime untranslated regions (UTRs), failed to detect anomalies in 14 of the 20 patients. Among these 14 patients, 10 represented familial cases, and, for 6 of them, linkage analysis was consistent with the involvement of EYA1. Since no evidence for genetic heterogeneity had been reported, Abdelhak et al. (1997) assumed that, for these 14 patients, the mutations were located either in the promoter region, within an intron, in the 3-prime UTR, or in the most 5-prime sequences which had not yet been studied extensively. This report brought the total number of mutations detected in BOR patients to 14; all of them were different. A common feature of the mutations, however, was their location within or in the immediate vicinity of the eyaHR (also called Eya box). The region of clustering of mutations represents half of the coding sequence. Mutations outside this domain may give rise to either a lethal defect or to a discrete undetected phenotype. Abdelhak et al. (1997) favored the latter hypothesis for the following reasons: 1 of the 2 patients carrying a deletion of the whole gene was exclusively affected by the BO syndrome (Haan et al., 1989), and the only mutation that had been detected outside the eyaHR was also present in a BOR-affected patient (601653.0004).
Kumar et al. (1998) identified 3 novel mutations in the EYA1 gene in patients with the BOR syndrome, 1 of which was a 4-bp deletion in a family originally reported by Rowley (1969). Kumar et al. (1998) found reports of 20 mutations in the EYA1 gene, most of them clustered in the C-terminal region (exons 9 to 16), in cases of BOR syndrome. Rickard et al. (2000) identified mutations in 11 of 18 individuals with classic BOR. They found no mutations in individuals with atypical BOR syndrome or OTFC syndrome. The mutations identified were clustered in exons 9 to 16 with 3 in exon 8 and 1 in exon 5.
Vervoort et al. (2002) noted that in up to one-half of reported cases of BOR syndrome, EYA1 screening was negative, suggesting genetic heterogeneity. Using SSCP and direct sequencing, they screened the coding region of the EYA1 gene in a panel of BOR families linked to chromosome 8. Only 1 point mutation in 5 probands was detected. However, using Southern blot analysis, complex rearrangements such as inversions and large deletions were identified in the other 4 patients. Vervoort et al. (2002) concluded that more complex rearrangements may have been missed in earlier studies, which commonly used only SSCP and sequencing for mutation detection.
Chang et al. (2004) sought to refine the clinical diagnosis of BOR syndrome by analyzing phenotypic data from families segregating EYA1 disease-causing mutations. Based on genotype-phenotype analyses, they proposed new criteria for the clinical diagnosis of BOR syndrome. The authors found that in approximately 40% of patients meeting their criteria, EYA1 mutations were identified. Of these mutations, 80% were coding sequence variants identified by SSCP, and 20% were complex genomic rearrangements identified by a semiquantitative PCR-based screen. Chang et al. (2004) concluded that genetic testing of EYA1 should include analysis of the coding sequence and a screen for complex rearrangements.
Migliosi et al. (2004) used an analysis based on denaturing high performance liquid chromatography (DHPLC) to identify 5 novel mutations in the EYA1 gene associated with BOR syndrome.
Orten et al. (2008) identified 70 different EYA1 mutations in 89 of 435 families with BOR or a related phenotype. EYA1 mutations were found in 76 (31%) of 248 families fitting established clinical criteria for BOR and 13 (7%) of 187 families with a questionable BOR phenotype. Most of the mutations were private, and there were no apparent genotype/phenotype correlations.
Stockley et al. (2009) identified EYA1 mutations (see, e.g., 601653.0016) in 14 (82%) of 17 unrelated probands with BOR syndrome. De novo mutations were confirmed in 45% of the patients.
In a patient carrying a mutation in the SIX5 gene (T552M; 600963.0004), Krug et al. (2011) identified a mutation in the EYA1 gene, a deletion removing exons 3, 4, and 5. This patient's DNA had been tested for EYA1 mutations by direct sequencing, but not for abnormal copy number. This observation, in addition to the extreme rarity of SIX5 mutations, caused Krug et al. (2011) to reconsider the role of SIX5 in branchiootorenal syndrome etiology.
Branchiootic Syndrome 1
To address the question of whether the branchiootic syndrome (BOS1; 602588) is the same as branchiootorenal dysplasia, Vincent et al. (1997) studied 2 large kindreds in each of which 8 affected members presented exclusively with BO syndrome (without the association of renal anomalies). In both kindreds, linkage analysis mapped the causative gene to the same chromosomal region as the EYA1 gene. A search for mutations in 9 of the EYA1 coding exons identified a 2-bp insertion (601653.0003) segregating in 1 family, and an 8-bp deletion (601053.0004) segregating in the other. Thus, the BOR and BO syndromes are allelic defects in the EYA1 gene.
Anterior Segment Anomalies
Azuma et al. (2000) examined genomic DNA isolated from patients with various types of developmental eye anomalies for EYA1 mutations by the use of PCR-SSCP and sequencing. They identified 3 novel missense mutations in patients who had congenital cataracts and ocular anterior segment anomalies (see 601653.0008-601653.0010). One of the patients had clinical features of BOR syndrome as well (see 601653.0010). These results implied that the human EYA1 gene is also involved in eye morphogenesis, and that a wide variety of clinical manifestations may be caused by EYA mutations. Mutations were heterozygous in all 3 probands; 2 of the 3 were sporadic.
Otofaciocervical Syndrome
Rickard et al. (2001) presented evidence that the otofaciocervical syndrome (OTFCS1; 166780) is a contiguous gene deletion syndrome involving the EYA1 gene, which is the site of mutations causing the branchiootorenal syndrome. They speculated that the differences between the 2 syndromes might be related to undefined genes included in the deleted region accounting for additional traits seen in OTFCS. Estefania et al. (2006) reported a patient with a splice site mutation in the EYA1 gene (601653.0014) and clinical changes thought to be characteristic of OTFCS, namely, alterations of the face and shoulder girdle in addition to malformations seen in BOR.
Johnson et al. (1999) described a spontaneous mutation causing deafness and circling behavior in a C3H/HeJ colony of mice. Pathologic analysis of mutant mice showed gross morphologic abnormalities of the inner ear, and also dysmorphic or missing kidneys. The deafness and abnormal behavior were shown to be inherited as an autosomal recessive trait, and were mapped to chromosome 1, near the position of the Eya1 gene (Xu et al., 1997). Molecular analysis of the Eya1 gene in mutant mice revealed insertion of an intracisternal A particle (IAP) element in intron 7. The presence of the IAP insertion was associated with reduced expression of the normal Eya1 message and formation of additional aberrant transcripts. The hypomorphic nature of the mutation may explain its recessive inheritance, if protein levels in homozygotes, but not heterozygotes, are below a critical threshold needed for normal developmental function. Johnson et al. (1999) designated the new mouse mutation Eya1(bor) to denote that it appears to be an authentic model of the human BOR syndrome.
In mice, Floyd et al. (2003) studied the modifier-of-vibrator-1 locus (Mvb1), which controls levels of correctly processed mRNA from genes mutated by endogenous retrovirus insertions into introns, such as occurs in the Eya1(BOR) model of human branchiootorenal syndrome. By positional complementation cloning, they identified Mvb1 as the nuclear export factor Nxf1 (602647), providing an unexpected link between the mRNA export receptor and pre-mRNA processing.
To understand the developmental pathogenesis of organs affected in BOR syndrome and BO syndrome, Xu et al. (1999) inactivated the Eya1 gene in mice. Eya1 heterozygotes showed renal abnormalities and a conductive hearing loss similar to BOR syndrome, whereas Eya1 homozygotes lacked ears and kidneys due to defective inductive tissue interactions and apoptotic regression of the organ primordia. Inner ear development in Eya1 homozygotes arrested at the otic vesicle stage, and all components of the inner ear and specific cranial sensory ganglia failed to form. In the kidney, Eya1 homozygosity resulted in an absence of ureteric bud outgrowth and a subsequent failure of metanephric induction. Gdnf (600837) expression, which is required to direct ureteric bud outgrowth via activation of the RET receptor tyrosine kinase (164761), was not detected in Eya1 -/- metanephric mesenchyme. In Eya1 -/- ear and kidney development, Six (see SIX1; 601205) but not Pax (see PAX2; 167409) expression was Eya1 dependent, similar to a genetic pathway elucidated in the Drosophila eye imaginal disc. The results indicated that EYA1 controls critical early inductive signaling events involved in ear and kidney formation, and integrated EYA1 into the genetic regulatory cascade controlling kidney formation upstream of GDNF. In addition, the results suggested that an evolutionarily conserved PAX-EYA-SIX regulatory hierarchy is used in mammalian ear and kidney development.
Li et al. (2003) reported that Six1 is required for the development of murine kidney, muscle, and inner ear and that it exhibits synergistic genetic interactions with Eya factors. Li et al. (2003) demonstrated that the Eya family has a protein phosphatase function, and that its enzymatic activity is required for regulating genes encoding growth control and signaling molecules, modulating precursor cell proliferation. The phosphatase function of Eya switches the function of Six1-Dach (603803) from repression to activation, causing transcriptional activation through recruitment of coactivators. The gene-specific recruitment of a coactivator with intrinsic phosphatase activity provides a molecular mechanism for activation of specific gene targets, including those regulating precursor cell proliferation and survival in mammalian organogenesis. Eya1 +/- Six1 +/- double heterozygous mice had a defect in kidney development, which was not observed in single heterozygotes for either gene deletion, suggesting that Six1 and Eya1 act in the same genetic pathway. Notably, there was a complete absence of all hypaxial muscle in Six1 -/- Eya1 -/- double knockout mice and severe reduction of epaxial muscle, a phenotype resembling that seen in mice homozygous for deletion of Myog (159980) and in double knockouts for MyoD (159970)/Myf5 (159990) and Pax3 (606597)/Myf5. Interestingly, although mutation of Six1 or Eya1 has minimal or no effect on pituitary development, mice with both genes deleted have a pituitary that is approximately 5- to 10-fold smaller by volume than the wildtype gland.
In a familial case of BOR syndrome (BOR1; 113650), Abdelhak et al. (1997) demonstrated a C-to-T transition of nucleotide 823 in exon z, resulting in a change of codon 275 from arginine to stop.
In a familial case of BOR syndrome (BOR1; 113650), Abdelhak et al. (1997) demonstrated substitution of 1251T with CC in exon D, resulting in a frameshift and premature termination of transcription.
In a kindred in which 8 members in 3 generations had the branchiootic syndrome (BOS1; 602588) (without renal anomalies), Vincent et al. (1997) demonstrated linkage to the same region of chromosome 8 where the EYA1 gene is located. Furthermore, they demonstrated a 2-bp (GT) insertion in exon A, at position 870.
In a family with 8 living members in 3 generations showing BO syndrome (BOS1; 602588), Vincent et al. (1997) demonstrated an 8-bp deletion at position 297 (297del8) of the EYA1 gene. The mutation resulted in a frameshift leading to a premature stop codon.
In a mother and daughter with BOR syndrome (BOR1; 113650), Abdelhak et al. (1997) demonstrated that the EYA1 gene carried an inserted Alu element in exon 10. The inserted element was in opposite orientation to that of the gene itself, and the 3-prime sequence of the Alu element was followed by a long poly(A) tail. The features were entirely consistent with retrotransposition. A difference in length of the poly(A) tail, which was reduced from poly(A)97 to poly(A)31 when transmitted from mother to daughter, demonstrated instability. The transposition was a de novo insertion as it was not present in the DNA from the maternal grandparents.
In a family reported originally by Rowley (1969), Kumar et al. (1998) demonstrated association of the BOR syndrome (BOR1; 113650) with a 4-bp deletion at nucleotide 1501 of the EYA1 gene.
In a case of familial BOR syndrome (BOR1; 113650), Kumar et al. (1998) identified a G-to-A transition at nucleotide 1220 in exon 12, resulting in an arg407-to-gln substitution.
In a 4-year-old Japanese girl with congenital cataracts and ocular anterior segment anomalies (see BOS1, 602588), Azuma et al. (2000) found an A-to-G transition at position 1688 of the cDNA corresponding to the EYA1 gene, expected to result in an arg514-to-gly amino acid substitution. Ocular examinations revealed central corneal opacity, adhesion to the iris (Peters anomaly), and slight cataracts in both eyes, whereas the fundus was normal. Her mother, aged 32, had nuclear-type congenital cataracts. The patient and her mother were otherwise normal in appearance, intelligence, and karyotype. No clinical findings suggesting BO/BOR syndrome were detected except for a slight elevation of the auditory brainstem response (ABR) threshold in hearing.
In a 3-year-old Japanese boy with an iris anomaly (see BOS1, 602588), Azuma et al. (2000) found a glu330-to-lys mutation due to a G-to-A transition at position 1136 (exon 10) of the EYA1 gene. The mutation was not detected in his parents, who were apparently normal. Examinations revealed bilateral persistence of the pupillary membrane, but a normal lens and fundus. He had no other systemic abnormalities and was found to be normal in growth and intelligence for his age.
Azuma et al. (2000) identified a gly393-to-ser mutation in an 8-year-old boy who first presented at their hospital with nystagmus and systemic edema at 20 days of age. Examinations revealed bilateral nuclear-type congenital cataracts with a normal fundus, and multicystic dysplasia in his right kidney, which did not function and caused hypocalcemia. The cataracts were operated on at 1 month of age and the right kidney was removed at 2 months. He was later found to have conductive deafness with the malleus anomaly. He also had cervical fistula that occluded spontaneously. Except for the cataracts, the clinical findings were considered typical of BOR syndrome (BOR1; 113650).
In a patient with classic BOR syndrome (BOR1; 113650) with a single kidney, Rickard et al. (2000) identified a 1-bp insertion at nucleotide 387 in exon 5 of the EYA1 gene. The authors concluded that mutations located outside exons 9 to 16 do not appear to result in different renal manifestations.
In a family with BOR syndrome (BOR1; 113650), Abdelhak et al. (1997) identified a ser454-to-pro (S454P) mutation in exon 13 of the EYA1 gene.
In a family with BOR syndrome (BOR1; 113650), Abdelhak et al. (1997) identified a leu472-to-arg (L472R) mutation in exon 14 of the EYA1 gene.
In a patient thought to have otofaciocervical syndrome (OFC1; 166780), Estefania et al. (2006) found a de novo heterozygous nucleotide substitution at the beginning of intron 6 of the EYA1 gene (540+1G-A). The patient had bilateral conductive hearing loss, a long and narrow face, preauricular and cervical pits, prominent and cupped ears, a high-arched palate, sloping shoulders and clavicles, and trapezius hypoplasia which allowed adduction of the shoulders. Chest x-ray showed diastasis of the right sternoclavicular joint, and urography demonstrated bilateral sponge kidneys.
In an infant with a variant form of branchiootic syndrome (BOS1; 602588), Spruijt et al. (2006) identified a heterozygous 982C-T transition in exon 10 of the EYA1 gene, resulting in an arg328-to-ter (R328X) substitution predicted to lead to a nonfunctional protein. The patient had severe obstructive sleep apnea caused by laryngomalacia, pharyngomalacia, glossoptosis, and tracheobronchomalacia. He also had retrognathia, bilateral branchial fistulae, ear anomalies, including ear pits, simple helices, and slight cup-shaped and low-set left ear. His mother, who also carried the mutation, had mild retrognathia, left-sided branchial neck fistula, left-sided preauricular pit, and right-sided branchial cyst in the neck. Kidney ultrasound and hearing were normal in both the mother and son. The findings expanded the phenotypic anomalies of BO syndrome associated with EYA1 mutations.
Olavarrieta et al. (2008) identified a de novo R328X mutation in the EYA1 gene in a Spanish man with branchiootorenal syndrome (BOR1; 113650). He had branchial fistulae, preauricular pits, renal agenesis, and mixed hearing loss. In addition, he had myopia, vitreous anomaly, flat face, and cleft palate, characteristic of Stickler syndrome type I (STL1; 108300) and was found to also carry a mutation in the COL2A1 gene (120140). Olavarrieta et al. (2008) emphasized that both disorders show phenotypic variability as well as overlapping features, which can complicate a precise diagnosis. Thorough clinical evaluation is necessary to identify coexisting genetic syndromes in the same patient.
In a Japanese girl with features of the branchiootic syndrome (BOS1; 602588), Shimasaki et al. (2004) identified a heterozygous 7-bp deletion (1402delACAACTA) in exon 14 of the EYA1 gene, resulting in a frameshift and premature termination of the protein at codon 483. The child had preauricular pits, cupped ears, hearing loss, and bilateral cysts over the sternocleid muscle. The mutation was most likely transmitted by the mother, who also had features of the branchiootic syndrome, although this was not confirmed by molecular testing. The patient also had features consistent with the Cayler cardiofacial syndrome (125520), including asymmetric facies while crying and a large patent ductus arteriosus. Shimasaki et al. (2004) suggested that the BO syndrome and Cayler syndrome may represent a spectrum of diseases.
In affected members of 3 of 17 unrelated families with BOR syndrome (BOR1; 113650), Stockley et al. (2009) identified a heterozygous G-to-A transition in intron 8 of the EYA1 gene (867+5G-A), resulting in a transcript lacking exon 8, predicting a frameshift and premature termination within exon 9. The mutation was not found in 100 control chromosomes. The same mutation was also found in 2 additional unrelated BOR probands outside of the original cohort. Haplotype analysis did not indicate a founder effect. RT-PCR analysis showed that the transcript produced by the splice site mutation escaped nonsense-mediated mRNA decay and produced a truncated protein containing only the N-terminal coactivator region, but not the C-terminal phosphatase domain. Stockley et al. (2009) suggested that this resulted in a combination of dominant-negative gain of function and haploinsufficiency. The renal phenotype was severe in affected individuals, including renal agenesis, structural abnormalities, and renal artery dysplasia.
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