At 9 to 10 days of age Whrnwi homozygotes display increased activity, decreased ability to right their selves, and are generally smaller than unaffected siblings. By 14 to 16 days of age homozygotes display head bobbing, circling, and an unsteady gate. Adults display head tossing and circling behavior and deafness is indicated by 20 days of age. Sackler and Weltman reported the average number of circles by a prodded 12-week old female homozygote to be 407 in 10 minutes. They found female homozygotes to have an increased metabolic rate and adrenocorticosteroid activity and decreased body weights. Homozygous males were reported to have decreased blood glucose and liver glycogen levels, decreased white blood cell and eosinophil counts, increased plasma albumin levels, and decreased globulin levels, in addition to decreased weight and increased food intake. (Lane 1963; Sackler and Weltman 1967, 1970, 1971.)
While the organ of Corti in whirler homozygotes shows normal gross cellular architecture at postnatal day (P) 35, stereocilia are shorter and stubbier. The inner hair cells have shorter stereocila as early as embryonic day (E) 18.5, are less than half the length of wild type by P5, and the normal graded variation in length and width along stereocilia ranks is diminished. While normal outer hair cell stereocillia develop a W-shaped array of ranks with a basal to apical increase in length, the outer hair cell stereocilia in whirler homozygotes develop a U-shaped or V-shaped array and the variation in length is diminished. The outer hair cells begin to degenerate by P60 while inner hair cells take longer to show degeneration, but both are undergoing degeneration by P80. (Kiernan et al., 1998; Holme et al., 2002.)
The wi mutation arose spontaneously in approximately 1955 in a multiple recessive stock homozygous for a, Tyrp1b, Myo5ad, Oca2p, and Ednrbs in the laboratory of Dr. Meredith N. Runner. This was the HO stock received from Dr. Holman. The phenotype was initially identified in a single male that was then outcrossed to C57BL/6J and the offspring were intercrossed once, non-sibling intercrossed once, then sibling mated to F5 before being maintained by backcross-intercross to C57BL/6J until N7. They were then maintained primarily by sibling intercross with occasional backcross to a parent until they were transferred to Dr. Eva Eicher in 1971. This strain has been maintained with Whrnwi in coupling with Tyrp1b from the original stock background on which the Whrnwi mutation arose. In 1981 N15F8 Whrnwi Tyrp1b/Whrnwi Tyrp1b males were bred with C57BL/6J females to generate embryos for cryopreservation.
|Gene Symbol and Name||Whrn, whirlin|
|Strain of Origin||STOCK a Tyrp1b Myo5ad Oca2p Ednrbs|
|General Note||They have defects of the membranous labyrinth similar to those of Myo15 (M.S. Deol, personal communication).|
|Molecular Note||The mutation was identified as a 526 bp deletion encompassing the first putative methionine of the short C-terminal isoform and part of the long isoform. This creates a frameshift resulting in premature termination of the long isoform before the third PDZ domain. This deletion encompasses the majority of exons 6-10 of the gene, thus resulting in the ablation of both the long (WHRN-L) and the short (WHRN-S) isoforms.|
|Gene Symbol and Name||Tyrp1, tyrosinase-related protein 1|
|Strain of Origin||old mutant of the mouse fancy|
|Molecular Note||A G-to-A transition point mutation at position 329 was shown by revertant analysis to be responsible for the mutant phenotype seen in the brown mutant. This mutation changes cysteine to tyrosine at position 110 (p.C110Y) in the encoded protein. Three other point mutations in the brown sequence were identified, but do not contribute to the mutant phenotype.|
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