| First Author | Harris BS | Year | 2016 |
| Journal | MGI Direct Data Submission | Mgi Jnum | J:229303 |
| Mgi Id | MGI:5751443 | Citation | Harris BS, et al. (2016) Two spontaneous alleles of Celsr1. MGI Direct Data Submission |
| abstractText | The recessive mutation curly tail bobber (Celsr1<ctb>) arose spontaneously in the CByJ.Cg-Foxn1<nu>/J strain at The Jackson Laboratory. Homozygotes may display head tossing, circling, otitis media, hearing impairment, abnormal hair pattern, curled/wavy tail or small size in comparison to littermates. The fur, most noticeably on the rump, can grow in reverse orientation leading to an overall ruffled coat appearance. The phenotype varies from animal to animal. Some mice that exhibited only small body size and wavy tails proved to be homozygotes, and the head bobbing and circling phenotypes also range from severe to mild. Homozygotes seldom breed, although they do live a normal lifespan. Histology on two males at ten months of age found otitis media, testicular atrophy and mild hydrocephalus. Cross sections of ears from three homozygotes found otitis media in all three and auditory brainstem response (ABR) analysis at four and five weeks of age found moderate to severe hearing loss. No hearing loss or abnormal phenotype was found in heterozygotes. Intercrossing heterozygotes yields less than 21% homozygotes rather than the expected 25%: of 311 total pups 246 were normal, 49 homozygous, 3 were born dead and 13 were missing or found dead. The average litter size is 5.76 pups. A mapping cross to CAST/EiJ mapped the critical interval to Chromosome 15 between 76,180,000 bp and 95,180,000 bp. Whole exome sequencing identified a single nucleotide deletion (G) at Chromosome 15 position 85,959,170 bp (GRCm38), which is predicted to result in a frameshift mutation in Celsr1. This deletion was found to segregate with the mutant phenotype. The curled tail, abnormal hair growth orientation, ear /vestibular defects and embryonic/perinatal lethality of curly tail bobber is consistent with the phenotypes of a targeted null Celsr1 mutant (Ravni et al., 2009 J Invest Dermatol 129(10):2507-9) and heterozygotes of semi-dominant ENU-induced Celsr1 point mutations (Curtin et al. 2003 Curr Biol 13:1129-33). A second spontaneous mutation with the same phenotype arose independently in the CBy.A-Ttc7<fsn>/J strain and was proven allelic with Celsr1<ctb> by a failed complementation test. This has been designated curly tail bobber 2 Jackson, Celsr1<ctb-2J>. The single G deletion of Celsr1<ctb> is absent from Celsr1<ctb-2J> mice. The original founder parents of the ctb-2J mutation had 6 affected mice in 57 born (10.5 % affected progeny), which is much less than the expected 25%, and subsequently the colony had less than 15% affected mice produced. Of 474 pups in 88 litters, 406 were normal, 60 homozygous, 1 was born dead and 7 were missing or found dead. The average litter size is 5.39 pups. Histology found testicular atrophy, giant nuclei in the epididymis, and mild hydrocephalus in one four-month-old and one six-month-old male and the six-month-old male had an atrophic thymus. Histology focused on the ears found otitis media in all ears assessed from six weeks to six months of age and ABR analysis found moderate to severe hearing loss as early as five-and-a-half weeks of age, the earliest time point assessed. X-rays of a six-week-old male and a twenty-two week old female found no skeletal abnormalities aside from the misshapen tail vertebrae. |
