Inner Ear and Kidney Anomalies Caused by IAP Insertion in an Intron of the Eya1 Gene in a Mouse Model of BOR Syndrome

Abstract

A spontaneous mutation causing deafness and circling behavior was discovered in a C3H/HeJ colony of mice at the Jackson Laboratory. Pathological analysis of mutant mice revealed gross morphological 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 mapped to mouse chromosome 1 near the position of the Eya1 gene. The human homolog of this gene, EYA1, has been shown to underly branchio-oto-renal (BOR) syndrome, an autosomal dominant disorder characterized by hearing loss with associated branchial and renal anomalies. Molecular analysis of the Eya1 gene in mutant mice revealed the 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. The new mouse mutation is designated Eya1(bor) to denote its similarity to human BOR syndrome, and will provide a valuable model for studying mutant gene expression and etiology.

Molecular Genetics of Vestibular Organ Development

“…A hypomorphic allele of Eya-1 has also been identified. In this case, the vestibular portion of the inner ear appears intact but the cochlear duct is truncated, suggesting that Eya-1 is particularly essential for cochlear development (Johnson et al 1999).…”

A natural allele of Nxf1 suppresses retrovirus insertional mutations

“…We show that suppressing Mvb1 alleles elevate steady-state level of correctly processed pitpn mRNA derived from vibrator mutant alleles, creating an in vivo titration of this gene product. We show that Mvb1 also modifies Eya1 BOR , a model of human branchiootorenal dystrophy caused by insertion of an IAP element (the class most frequently associated with spontaneous mutations in mice) inserted into introns in the sense orientation 5 . We identify Mvb1 by a positional complementation strategy as an allele of the mRNA nuclear export factor Nxf1.…”

“…An IAP insertion into an intron reduces the level of host gene expression ~50% 5 . Homozygous animals have a pronounced cochlear malformation and can be recognized behaviorally by characteristic head bobbing, circling, and failure to startle in response to loud noise.…”

“…Mvb1 also modifies Eya1 BOR mortality, caused by kidney dysgenesis/agenesis on the C3H genetic background 5,9 . Among 93 F2 Eya1 BOR /Eya1 BOR animals from a second cross (C3H-Eya1 BOR × CAST/Ei), we find a significant absence of C3H homozygotes at Mvb1 (14/93; p>0.01, chi-square test), and a slight excess of CAST homozygotes (35/93) relative to Mvb1 heterozygotes (44/93).…”

Development of the zebrafish inner ear

“…Loss of cristae; abnormal maculae, semicircular canal system and neurogenesis; cell death (Whitfield et al, 1996;Kozlowski et al, in preparation) Eya1 bor (Johnson et al, 1999); targeted disruption (Xu et al, 1999) Branchio-Oto-Renal syndrome (Abdelhak et al, 1997) jekyll (jek) ugdh1 (Walsh and Stainier, 2001) UDP-glucose dehydrogenase (sugarless)…”