Disease relevance of EYA1

• Clustering of mutations responsible for branchio-oto-renal (BOR) syndrome in the eyes absent homologous region (eyaHR) of EYA1 [1].
• Mutations of a human homologue of the Drosophila eyes absent gene (EYA1) detected in patients with congenital cataracts and ocular anterior segment anomalies [2].
• Genetic features of hearing loss associated with ear anomalies: PDS and EYA1 mutation analysis [3].
• We investigated the presence of EYA1 mutation in two unrelated patients with autosomal dominant hereditary deafness and congenital preauricular fistula [4].
• Identification of a novel EYA1 mutation presenting in a newborn with laryngomalacia, glossoptosis, retrognathia, and pectus excavatum [5].

Psychiatry related information on EYA1

• In the first study, 226 women were administered the Personality Assessment Inventory, borderline scales (PAI-BOR; L.C. Morey, The Personality Assessment Inventory, Professional Manual, 1991) and a questionnaire that assessed time in menstrual cycle and use of oral contraceptives, that is synthetic estrogens [6].

High impact information on EYA1

• Haploinsufficiency for human EYA1, a homologue of the Drosophila melanogaster gene eyes absent (eya), results in the dominantly inherited disorders branchio-oto-renal (BOR) syndrome and branchio-oto (BO) syndrome, which are characterized by craniofacial abnormalities and hearing loss with (BOR) or without (BO) kidney defects [7].
• The expression pattern of the murine EYA1 orthologue, Eya1, suggests a role in the development of all components of the inner ear, from the emergence of the otic placode [8].
• The role of protein in pancreatic carcinogenesis was examined in outbred Syrian golden hamsters treated with the pancreatic carcinogen N-nitrosobis(2-oxopropyl)amine (BOP) and fed a purified protein-free diet (PPFD) [9].
• The effect of acute and recurrent pancreatitis was investigated in pancreatic cancer induction by N-nitrosobis(2-oxopropyl)amine (BOP) in Syrian golden hamsters [10].
• The effects of dietary fat on carcinogenesis were presented, with the pancreas excluded, in randombred Syrian golden hamsters after administration of N-nitrosobis(2-oxopropyl)amine (BOP) [11].

Chemical compound and disease context of EYA1

• The ability of a boronated porphyrin, 2,4-(alpha, beta-dihydroxyethyl) deuteroporphyrin IX tetrakiscarborane carboxylate ester (BOPP), to act as a photosensitizing agent was investigated in vitro with the C6 rat glioma cell line and in vivo with C6 cells grown as an intracerebral tumor after implantation into Wistar rats [12].
• Ratios of N7-methylguanine in BOP versus HPOP treated hamsters, at doses less than 40 mg/kg body weight, were 3.1 in the kidney, 7.0 in the pancreas, 3.9 in the lung, and only 3.5 in the liver [13].
• Six weeks after SZ treatment, all hamsters were treated with BOP (10 mg/kg body weight) weekly for 10 weeks and the experiment was terminated 38 weeks after the last BOP treatment [14].
• Oltipraz at 300 mg/kg had no effect on the incidence or multiplicity of preneoplastic, neoplastic or metastatic lesions, while at 600 mg/kg dietary Oltipraz the incidence of pancreatic adenocarcinomas was reduced significantly (P < or = 0.05) compared to BOP-treated controls [15].
• The total numbers of pancreatic lesions comprising carcinomas, atypical ductal hyperplasias and ductal hyperplasias per hamster were significantly decreased in animals receiving BOP followed by CC, HQ and RN when compared to those in hamsters given BOP followed by basal diet [16].

Biological context of EYA1

• Among these mutations, two are missense mutations, highlighting amino acid residues essential for the function of the EYA1 protein, and one mutation comprises a de novo Alu insertion into an exon [1].
• However, it remains unknown whether Pax genes interact with Eya1 or Six1 during inner ear morphogenesis [17].
• We report here that Eya1(-/-) otic epithelium shows reduced cell proliferation from E8.5 and increased cell apoptosis from E9.0, thus providing insights into the cellular basis of inner ear defect which occurred in the absence of Eya1 [17].
• Recently, several point mutations that result in single amino acid substitutions in the conserved Eya domain region of EYA1 have been identified in BOR patients; however, the molecular and developmental basis of organ defects that occurred in BOR syndrome is unclear [18].
• Mutation screening of the coding region of EYA1 in a panel of families linked to chromosome 8 was conducted using SSCP and direct sequencing [19].

Anatomical context of EYA1

• Eya1 regulates the growth of otic epithelium and interacts with Pax2 during the development of all sensory areas in the inner ear [17].
• In contrast, a human homologue, EYA1, has been identified by positional cloning as a candidate gene for branchio-oto-renal (BOR) syndrome, in which phenotypic manifestations are restricted to the areas of branchial arch, ear and kidney, with usually no anomalies in the eye [2].
• PDS mutations were found only in patients with enlarged vestibular aqueducts and EYA1 mutations were detected only in patients with ear pits and cervical fistulae, indicating that these two genes are associated with particular forms of middle and inner ear malformation [3].
• Intensive induction-sequential chemotherapy with BOP/VIP-B compared with treatment with BEP/EP for poor-prognosis metastatic nonseminomatous germ cell tumor: a Randomized Medical Research Council/European Organization for Research and Treatment of Cancer study [20].
• However, in contrast to BOP, which was noncarcinogenic to the upper respiratory tract, MOP-treated animals developed a high incidence of nasal cavity tumors (40% after a single treatment and 27 to 100% after weekly injections) [21].

Associations of EYA1 with chemical compounds

• The data show that BOPP is more dose effective in vivo by a factor of 10 than the current clinically used photosensitizer hematoporphyrin derivative and suggest that BOPP may have potential as a dual PDT/BNCT sensitizer [12].
• 7-Methylguanine was found in hydrolysates of liver and pancreas DNA from Syrian golden hamsters given a single dose of N-[1-14C]nitrosobis(2-oxopropyl)amine (BOP) [21].
• PATIENTS AND METHODS: In a phase III study patients received six cycles of BEP/EP (etoposide, and cisplatin, plus or minus bleomycin) or six cycles of BOP/VIP-B (bleomycin, vincristine, cisplatin/etoposide, ifosfamide, cisplatin, bleomycin) [22].
• This led us to examine the carcinogenicity of a potential methylating metabolite of BOP, N-nitrosomethyl(2-oxopropyl)amine (MOP) [21].
• N-Nitrosobis(2-oxopropyl)amine (BOP) and N-nitroso(2-hydroxypropyl)(2-oxopropyl)amine (HPOP) alkylate DNA and other macromolecules in the liver, kidney, pancreas, and lungs when injected s.c. in the Syrian hamster [13].

Other interactions of EYA1

• While mutations in human EYA4 cause late-onset deafness at the DFNA10 locus, mutations in human EYA1 cause branchio-oto-renal (BOR) syndrome [17].
• We have examined genomic DNA isolated from patients with various types of developmental eye anomaly for EYA1 mutations by the use of polymerase chain reaction-single-strand conformation polymorphism and sequencing [2].
• To identify whether mutations in NDUFB9 are involved in causing the BOR syndrome, we screened 9 BOR families which did not show mutations in the EYA1 gene by heteroduplex analysis; however, no mutations were found [23].
• EYA1 and SIX1 gene mutations in Japanese patients with branchio-oto-renal (BOR) syndrome and related conditions [24].

Analytical, diagnostic and therapeutic context of EYA1

• Sequence analysis of the entire EYA1 coding region was performed for 20 unrelated patients affected by BOR syndrome, and six novel mutations were identified [1].
• A Danish BOR family with five affected individuals in three generations was analyzed for mutations in all 17 exons of EYA1 using direct sequencing of polymerase chain reaction (PCR) amplified genomic DNA [25].
• The results showed that BOP, when given during cellular degeneration (group 2) and healing (group 4), induced significantly fewer carcinomas than in the control groups, whereas the tumor pattern was not affected when BOP was given before pancreatitis induction (group 1) or at the time of cellular regeneration (group 3) [10].
• Additional groups received BOP 30 minutes before common duct ligation for 48 hours (group 1) or before repeated induction of pancreatitis at 4 weekly intervals for 4 weeks (group 5) [10].
• RESULTS: There was no significant difference between the two arms in the proportion of patients who achieved a complete response (CR) with chemotherapy alone, ie, 79 of 185 assessable patients (57%) with BEP/EP and 72 of 186 (54%) with BOP/VIP-B (P = 0.687) [20].

References