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Fine Mapping of the Circling (<I>Cir</I>) Gene on the Distal

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Fine Mapping of the Circling (<I>Cir</I>) Gene on the Distal Comparative Medicine Vol 53, No 6 Copyright 2003 December 2003 by the American Association for Laboratory Animal Science Pages 642-648 Fine Mapping of the Circling (cir) Gene on the Distal Portion of Mouse Chromosome 9 Kyoung In Cho, DVM,1, 2,* Jeong Woong Lee, PhD,1,* Kil Soo Kim, PhD,3 Eun Ju Lee,1 Jun-Gyo Suh, PhD,2 Ho-Joon Lee, PhD,4 Hyun Taek Kim, PhD,5 Sung Hwa Hong, MD,6 Won Ho Chung, MD,6 Kyu Tae Chang, PhD,7 Byung Hwa Hyun, PhD,7 Yang-Seok Oh, PhD,2,† and Zae Young Ryoo, PhD,1,† Circling mice manifest profound deafness, head-tossing, and bi-directional circling behavior, which they inherit in autosomal recessive manner. Histologic examination of the inner ear reveals abnormalities of the region around the organ of Corti, spiral ganglion neurons, and outer hair cells. A genetic linkage map was constructed for an intraspecific backcross between cir and C57BL/6J mice. The cir gene was mapped to a region between D9Mit116/ D9Mit15 and D9Mit38 on mouse chromosome (Chr) 9. Estimated distances between cir and D9Mit116, and between cir and D9Mit38 were 0.70 ± 0.40 and 0.23 ± 0.23 cM, respectively. Order of the markers was defined as follows: centromere - D9Mit182 - D9Mit51/D9Mit79/ D9Mit310 - D9Mit212/D9Mit184 - D9Mit116/D9Mit15 - cir - D9Mit38 - D9Mit20 - D9Mit243 - D9Mit16 - D9Mit55/D9Mit125 - D9Mit281. On the basis of genetic mapping, we constructed a yeast artifi- cial chromosome (YAC) contig across the cir region. The cir gene is located between the lactotransferrin (ltf) and microtubule-associated protein (map4) genes. The distal portion of mouse Chr 9 encompassing the cir region is homologous with human chromosome 3p21, which contains the Deafness, form B: Autosomal Recessive Deafness (DFNB6) locus. Therefore, the circling mouse is a potential animal model for DFNB6 deafness in humans. Over the past several years, the mouse has been used as a Table 1. Cloned genes for human nonsyndromic hearing impairment * model and, as such, has made substantial contributions toward (DFNB) our understanding of human developmental disorders. Muta- Gene Locus tions at different loci in humans and mice are known to cause Connexin 26 gene (GJB2) DFNB1 (13, 15) hearing impairment (5, 8, 13, 19, 29, 35, 36). In 70% of human Myosin 7A gene (MYO7A) DFNB2 (13, 35) cases, deafness is the sole clinical feature and is not accompa- Myosin 15 gene (MYO15) DFNB3 (10, 34) Pendred gene (PDS) DFNB4 (5, 29) nied by the broad clinical signs of disease that characterize the Transmembrane serine protease gene (TMPRSS3) DFNB8, DFNB10 (27) remaining 30% of syndromic deafness (21, 33). In recent years, Otoferlin gene (OTOF) DFNB9 (36) Cadherin-like gene (CDH23) DFNB12 (8) there has been a marked increase in the localization of genes for Alpha-tectorin gene (TECTA) DFNB21 (23) autosomal dominant and autosomal recessive nonsyndromic Claudin-14 gene (CLDN14) DFNB29 (37) hearing impairment (31). *Full name of each gene and its abbreviation are given, along with related DFNB Approximately one in every 1,000 individuals becomes deaf form. before adulthood, and about half of these cases are attributable to genetic defects of autosomal recessive deafness (DFNB). Al- cally, circling mice have cochlea degeneration and reduced cellu- though more than 30 DFNB loci have been mapped, only nine larity in the spiral limbus (7, 18). Results of an auditory test genes have been identified (31, Table 1). clearly documented hearing loss in the circling mouse (18). The circling mouse is a spontaneous mutant, with abnormali- Thus, the circling mouse is a useful model for the study of inner ties of the inner ear, that was first reported in Korea (18). The ear abnormalities and deafness. In the study reported here, a mutation is transmitted as an autosomal recessive trait, with cir locus for deafness was finely mapped, using microsatellite 100% penetrance. These mice become hyperactive at about markers. This genetic mapping not only facilitates positional seven days of age, then manifest circling behavior. Microscopi- cloning, but also will help to determine which, if any, human re- cessive deafness loci are homologues of cir. The cir gene has Received: 12/20/02. Revision requested: 2/21/03. Accepted: 7/17/03. been mapped to the central region between the D9Mit116/ 1Catholic Research Institutes of Medical Science, Catholic Medical College, 505 D9Mit15 and D9Mit38 loci on mouse Chr 9. The distal portion of Banpo-Dong, Seocho-Ku, Seoul 137-701, Korea, 2Department of Medical Genet- ics and Experimental Animal Center, College of Medicine, Hallym University, the mouse Chr 9 is syntenic with human Chr 3p21 (25). The hu- Chunchon 200-702, Korea, 3Department of Laboratory Animal Sciences, College man Chr 3p21 region includes the DFNB6 deafness region (11). of Medicine, Hanyang University, SEOUL 100-799, Korea, 4Eulji University, Therefore, the circling mouse may be an animal model of hu- Seoul, Korea, 5Department of Psychology, Korea University, Seoul, Korea, 6Sungkyunkwan University, Seoul, 135-710, Korea, and 7Biological Resource man DFNB6 deafness. Center, Korea Research Institute of Bioscience and Biotechnology, Oun-dong 52, Yusong-ku, Daejeon 305-333, Republic of Korea. *Corresponding authors who equally contributed to this report. Materials and Methods †These corresponding authors also equally contributed to this report. Mice. Circling mice were first discovered in an ICR out-bred 642 Fine mapping of the circling (cir) gene in mice strain, and have been maintained for 16 generations by matings murine cir gene. The mouse YAC clones were obtained from Re- between affected siblings in the Laboratory Animal Center, search Genetics Inc. and Bioneer Co. Extremities of YAC clones Catholic Research Institutes of Medical Science, Catholic Medi- were recovered by use of the vectorette PCR technique (26). Spe- cal College, Seoul, Korea. Circling C57BL/6J mice were used dur- cific bands generated by PCR analysis were cloned into pGEM-T ing this study. The C57BL/6J mice were obtained from the Korea Easy vector (Promega, Madison, Wis.) and sequenced by use of Research Institute of Bioscience and Biotechnology, Daejeon. SP6 primer in an automated DNA sequencer (Perkin Elmer). Mice were kept in a specific-pathogen-free conditioned animal Cloning of candidate genes. To identify potential genes for care facility. Genetic analyses were conducted with C57BL/6J deafness in the mouse, the conserved genes located within the cir mice as a normal control strain. Mice were free of the following region were amplified by use of primer pairs around the open microorganisms: Sendai virus, mouse hepatitis virus, Myco- reading frame of each gene. The primers used for the candidate plasma pulmonis, Tyzzer’s organism, Pasteurella pneumotropica, analysis were derived from GenBank. The sequence, size and Salmonella spp., Corynebacterium kutscheri, Pseudomonas BLAST accession number of tested genes are listed in Table 2. aeruginosa, and Bordetella bronchiseptica. Microbiological moni- Total RNA was extracted from tissues of C57BL/6J and cir/cir toring against the aforementioned microorganisms in circling mice, using Trizol reagent (Sigma Chemical Co., St. Louis Mo.). and C57BL/6J mice was conducted quarterly. Reverse transcriptase (RT)-PCR analysis was performed, using Mice were housed individually in plastic cages (18 × 30 × 15 the Superscript II pre-amplification system (GIBCO BRL. En- cm) with bed-o’cobs litter (The Andersons Inc. Maumee, Ohio), gland, UK ) according to supplied protocols. Samples were se- and were maintained in an air-conditioned (temperature, 22 to quenced only when bands of correct size were obtained. To 26°C, and humidity, 55 to 60%) and light-controlled (12 h light, isolate the PCR products, the fragments were cloned, using the 12 h dark: lights on/off; 7 a.m./7 p.m.) animal room. All mice pGEM-T Easy Vector System. The cDNA fragments were se- were allowed ad libitum access to rodent chow (No. 5001, quenced, and identity was established by use of BLAST. Purina Mills, Bethlehem, Pa.) and tap water. Chow, bedding, and tap water were sterilized by autoclaving prior to use. All Results animal studies were performed with the approval of the Experi- Clinical observations. All affected mice were clinically nor- mental Animal Care and Use Committee of Catholic University. mal at birth, but gradually manifested hyperactive behavior at The backcross progeny were generated by mating ICR females approximately seven days of age. At that age, shaking of the (+/+) with affected male (cir/cir) mice; then F1 female (cir/+) mice head was first observed, and became more conspicuous during were backcrossed to cir/cir males. Affected mutant mice could be the next three to four days. This pattern was easily noticed at 13 easily distinguished from normal phenotypic littermates (cir/+) or 14 days. The affected mice frequently ran in tight circles, es- by observation of head tossing, circling, and inability to swim at pecially when placed in strange surroundings or when other- postnatal day 10. About three weeks later, 428 backcross prog- wise disturbed. However, they did not have directional eny were collected for this study. preference when circling and were approximately twice as ac- Single-sequence length polymorphism (SSLP) analysis. tive as control mice. Linkage analyses were performed by using microsatellite mark- Genetic mapping of the cir gene. Genetic analyses were ers (purchased from Research Genetics, Inc., Huntsville, Ala.), conducted with C57BL/6J mice as a normal control strain. In using a modification of a described method (34). Polymerase test crosses with circling mice, mating of carrier with affected chain reaction (PCR) analysis for SSLP analysis was performed and affected with affected mice produced normal and affected for a subset of the 428 animals. All primer pairs were obtained offspring in the ratio of 1:1 (189:165) and 0:1 (0:24), respectively. from Research Genetics and Bioneer Co. (Daejeon, Korea). These results indicated that the trait is controlled by a single These microsatellites were amplified from 100 ng of template autosomal recessive gene with complete penetrance.
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