| First Author | Cruickshank JL | Year | 1991 |
| Journal | Mouse Genome | Volume | 89 |
| Pages | 568-70 | Mgi Jnum | J:14312 |
| Mgi Id | MGI:62483 | Citation | Cruickshank JL, et al. (1991) Tibialess (Tba): a new semi-dominant mutant in the mouse. Mouse Genome 89:568-70 |
| abstractText | Full text of Mouse Genome contribution: TIBIALESS (Tba): A NEW SEMI -DOMINANT MUTANT IN THE MOUSE J L CRUICKSHANK + , D R JOHNSON! and M E WALLACE*. +Department of Orthopaedic Surgery, St James's Hospital, Leeds. !Department of Anatomy, University of Leeds. *Department of Genetics, Cambridge. Mutations causing mirror image polydactly, ectrodactyly and hemimelia in the mouse are by no means uncommon (1): as a group they are of interest because the combination of these effects seen in a particular genotype and the fact that they are often differently expressed in fore or hind limbs suggests that different mutants may represent the subtly different mechanisms of embryonic development which underlie different adult phenotypes. Tibialess warrants description as an original combination of phenotypic entities. A single male with a deformed haunch appeared in a line being selected for an increased rate of chromosome damage. This was derived from an unselected inbred line descended from mice trapped at site 5, part of the pure wild Peru - Coppock. This stock is itself remarkable for its high rate of chromosome damage (2). The abnormal male and his descendants were crossed within the Peru stock and outcrossed to two other laboratory stocks, AG/Cam (an inbred line) and line 4 (a closed colony). Segregation ratios were recorded from affected x normal, reciprocal, and abnormal x abnormal crosses. Mice were classified at the age of 0 - 8 days. Fifty adult Tibialess mice and fifty normal littermates were examined under the dissecting microscope after being cleared and stained with alizarin red S (JLC,DRJ). The results of reciprocal crosses between affected and normal mice and crosses of affected x affected are given in Table 1. Affected females sometimes failed to rear whole Table 1. Segregation of Tibialess and normal mice. affected m x normal f: Affected: 148; Normal: 242; Total: 390; No of litters: 72; No dead 0-8 d: 8; Ratio tested: 1:1; X2: 25.27; p: <0.001. affected f x normal m: Affected: 14; Normal: 24; Total: 38; No of litters: 11; No dead 0-8 d: 2; Ratio tested: 1:1; X2: 25.27; p: <0.001. affected f x affected m: Affected: 102; Normal 82; Total: 184; No of litters: 43; No dead 0-8 d: 4; Ratio tested: 2:1; X2: 10.45; p: <0.01; Ratio tested: 3:1; X2: 37.56; p: <0.001. litters and so were used sparingly. In matings between affected and non - affected mice the ratio of abnormal:normal (presumed heterozygote:normal) differs significantly from the expected 1:l with a deficiency of abnormals. In abnormal x abnormal matings there is a very poor fit to the expected 3:l ratio, but a less poor fit to a 2:l ratio which assumes that the homozygous abnormal is a prenatal lethal. Thus there is a severe deficiency of abnormals from all types of mating. Litter size was small (affected x normal 5.2; affected x affected 4.3). Linkage was tested with hammer-toe and grey-coat (Hm, gc chromosome 5) and extreme non-agouti (ae, chromosome 2). A preliminary report has been given elsewhere (3). The results, presented in Table 2, give no indication of linkage. Table 2. Linkage test crosses. Hm+/+ Tba x ++/++; Mutants* tested: M +: 16; M Tba: 8; m +: 15; m Tba: 13; Total: 52; Ratio N;R: 29:23; X2 test!: 0.69; p value: >0.3. Tba +/+ ge x +ge/+ge; Mutants* tested: M +: 15; M Tba: 5; m +: 15; m Tba: 5; Total: 40; Ratio N;R: 20:20; X2 test!: 0.0; p value: 1.0. Tba+ /+ a x a/+a; Mutants* tested: M +: 45; M Tba: 14; m +: 42; m Tba: 19; Total: 120; Ratio N;R: 56:64; X2 test!: 0.53; p value: >0.3. Hm = hammer toe, gc = greycoat, Tba = tibialess; Mutants: 1st row: M = Hm, m = normal toes; 2nd row: M = normal coat, m = gc; 3rd row: M = A, m = a (non - agouti) or ae (extreme non -agouti) ! The X2 tests the equality of N (non - recombinants) with R (recombinants) in the previous column. The insignificant deficit of recombinants in the segregation with hammer-toe is more likely to be due to synergism between these skeletal mutants than to loose linkage. In 50 tibialess mice and 50 normal controls examined as alizarin clearance preparations no abnormality was seen in the forelimbs. In the hind limbs a series of abnormalities of varying severity was present. In some cases digit I was replaced by a digit with 3 phalanges (26 limbs: 15R;11L) or missing (38:17R;21L). In eight limbs digit I was represented by a proximal metatarsal splint (3R;5L). In a further 6 limbs digits I and II were affected (3R;3L), digit I being absent and digit II represented by a metatarsal splint, a claw plus the distal end of a phalanx or absent. Frank polydactyly was seen as a prehallux of claw plus distal part of phalanx in 3 limbs (all R). Soft tissue syndactyly (10:4R;6L) and bony syndactytiy (3:0R;3L) were seen occasionally. In addition the tibia was often absent (36:21R;15L), represented only by its proximal end (30:17R;13L) or thinned (2R). The fibula was almost universally bowed and thickened, often with evidence of healed fractures. The femur was involved three times, bilaterally in one individual and on the right side in the other. In the bilaterally affected individual the femora were represented by bony knobs: one on the left and two (femoral head + remainder?) on the right. The sciatic foramen was incomplete in all three cases. The segregation data presented above indicate that Tibialess behaves as a semi-dominant condition. In matings of normal x Tibialess individuals there was a significant deficit of Tibialess mice not accounted for by deaths between birth and classification by 8 days. We conclude that a proportion of Tba/ + Tibialess mice die between conception and birth. At and after birth there are further sporadic losses of affected individuals. Penetrance of the condition is complete, since there was never any difficulty in classifying individuals as normal or grossly abnormal, ie there were no intermediates. Assuming a perfect zygotic ratio of 1:l the number of deaths in our affected x normal matings (Table 1) is 104 or 0.39 of the expected zygotic number of heterozygotes. Similarly from the affected x affected matings a perfect zygotic ratio of 2:1 for heterozygotes to normal (assuming no surviving homozygotes) assumes 62 deaths or 0.38 of the expected zygotic number. A perfect zygotic ratio of 3:1 (assuming survival of homozygotes) would indicate 144 deaths or 0.58 of the affected ones. The close agreement in death rates where 1:l and 2:1 are expected proves the lethality of the homozygotes. The age of death of the heterozygotes is unknown, but must be mainly prenatal since classification, at birth only, produced few dead affected neonates (data not shown). The average litter sizes (5.2 for affected x normal, 4.3 for affected x affected) are slightly closer than expected with the 0.38 antenatal death rate. This would be expected if the homozygotes die early since this would reduce intrauterine competition and allow more heterozygotes to survive from the latter than from the former. The lack of linkage with markers on chromosomes 2 and 5 suggests that Tba is unlikely to be allelic with Strong's luxoid (lst, 4) or luxate (lx,5). Neither of these mutants is regularly lethal in homozygous form. A number of other conditions in the mouse produce syndromes comprising polydactyly, ectrodactyly, and hemimelia, often in different combinations or affecting different limbs (1). Tibialess resembles various members of this group in some aspects of the syndrome but not in others. For instance, like dominant hemimelia (Dh, 6), it is dominant with a lethal homozygous form (though Dh/Dh sometimes survive to breed). Extra - toes (Xt, 7) is also dominant with a prenatally lethal homozygote but expresses polydactyly rather than hemimelia in the heterozygote. Green's luxoid (lu, 8) is recessive but also affects the forelimbs. Tibialess produces a seemingly unique combination of dominant inheritance, a prenatal lethal homozygote and full penetrance. The usual minimal expression of triphalangy of the hallux or an extra preaxial digit without tibia1 involvement are absent in our sample. It seems likely that the stock of mutations affecting the limbs of mouse and chick reflect deviations in normal embryology. In the past (see 1 for summary) studies of mutants have complemented experimental embryology, and comparisons between mutant and normal limbs have produced much valuable data on normal development. Recent studies with homeobox genes have extended the potential greatly: we may well soon be able to spotlight the exact areas where a gene product has to be abnormally expressed in order to promote polydactyly or ectrodactyly. With this increase in resolution subtly different mutations may well enjoy increased utility and popularity. References (1) Johnson D R. 1986 The Genetics of the Skeleton. Clarendon Press, Oxford (2) Wallace M E. 1985 J. Hered. 76, 271-278. (3) Wallace M E. 1984 Mouse Newsletter, 71, 18-19. (4) Forsthoefel P F. 1962 J. Morpho1. 110, 391-420. (5) Carter T C. 1951 J. Genet. 50,277-299. (6) Searle A G. 1964 Genet. Res. 5, 171-197. (7) Johnson D R. 1967 J. Embryol. Exp. Morphol. 17, 543Ð581. (8) Green M C. 1955 J. Hered. 46, 91-99. |
