| First Author | Beechey C | Year | 1997 |
| Journal | Mouse Genome | Volume | 95 |
| Issue | 3 | Pages | 692-694 |
| Mgi Jnum | J:43275 | Mgi Id | MGI:1097455 |
| Citation | Beechey C, et al. (1997) Brachyrrine, BR, a mouse craniofacial mutant, maps to distal Chromosome 17 and is a candidate model for midline cleft syndrome. Mouse Genome 95(3):692-694 |
| abstractText | Full text of Mouse Genome contribution: BRACHYRRINE, BR, A MOUSE CRANIOFACIAL MUTANT, MAPS TO DISTAL CHROMOSOME 17 AND IS A CANDIDATE MODEL FOR MIDLINE CLEFT SYNDROME. Colin Beechey, Yvonne Boyd and Tony Searle. MRC Mammalian Genetics Unit, Harwell, Oxfordshire OX11 ORD, UK. The brachyrrhine (Br) mutation arose in a neutron irradiation experiment (1) and is an autosomal semidominant with postimplantation homozygote lethality. There is a marked shortage of heterozygotes in outcrosses and survivors are often small and characterised by a much shortened snout and a deeper than usual median cleft in the upper lip (1). Kidneys are small at birth and, in a number of Brl+ mice dying in early maturity, are extremely pale with very few glomeruli (1), almost no cortical tissue and an increase in interlobular connective tissue (2). Recent detailed morphometric studies suggest that in Br/+ mice, the growth pattern of the skull is abnormal in the anterior cranial base (3,4). No evidence for chromosomal deletion or duplication could be observed on cytological examination (Evans, pers. comm.). We report here the mapping of Br to distal chromosome 17 using a two-step approach. Visible marker genes and translocation breakpoints distributed over the genome were tested for linkage to Br. As none was found, microsatellite markers were then used to test the remaining regions in an interspecific backcross. Linkage tests with twenty seven marker genes and translocation breakpoints (Table 1) excluded Br from approximately two-thirds of the genome. From data presented in table 1, linkage of Br with Chrs 1, 2, 8, 10, 11, 13, 15, 16 and 19 is unlikely. Of the remaining chromosomal regions, distal 3, central 4, 5, 6, 7, 9, and distal 12, central 14, proximal 17 and proximal 18 also failed to show linkage with Br. Table 1. Markers and chromosomal regions showing no linkage with Br. Chromosome: 1; Marker(a): fz (6); ln (42); Chromosome: 2; Marker(a): T(2;4)13H(23); a(70); Chromosome: 3; Marker(a): ma (57); Va (87); Chromosome: 4; Marker(a): Tyrp1b(35); T(2;4)13H (40); Chromosome: 5; Marker(a): Ph (37); Chromosome: 6; Marker(a): Tgfawal(39); Chromosome: 7; Marker(a): Tyrc (42); Chromosome: 8; Marker(a): T(2;8)26H (17); Os (32); Mclre (61); Chromosome: 9; Marker(a): Myo5ad ; Bmp5se (38); Chromosome: 10; Marker(a): v (28); MgfSl (65); Chromosome: 11; Marker: wa2 (5); Re (55); Chromosome: 12; Marker: T(5;12)31H (72); Chromosome: 13; Marker: bg (17); Gli3Xt(18); sa (26); pe (54) Chromosome: 14; Marker: Ednrbs (37); Chromosome: 15; Marker: uw (0); Ca (57); Chromosome: 16; Marker: md (6), T(X; 16) 16H (47); Chromosome: 17; Marker: T (4); Chromosome: 18; Marker: Tw (11); Chromosome: 19; Marker: ep (30). (a) - The position of markers in cM from the centromere as depicted in the Mouse Chromosome Atlas (5) are given in parentheses. Approximately 50 mice were tested in each case. Full names of loci and details of translocations can be found in ref 6. An interspecific backcross was therefore established by mating affected (Br/+ x Mus spretus) Fl females to C3H/HeH x 101/H Fl males as Br is maintained on this C3H/HeH x 101/H Fl background. Fifty two backcross mice were scored at weaning, or shortly after, sacrificed and tail tips taken for DNA preparation and analysis. Initially, 8-12 backcross offspring were tested for linkage to amplification product variants (APVs) at D3Mit22, D3Mit46, D7Mit112, D7Mit47, D12Mit54, Dl7Mit39 and Dl8Mit8. Primers used for the detection of these loci were purchased from Research Genetics (Huntsville, Alabama) and polymerase chain reactions (PCRs) were carried out as described previously, using an annealing temperature of 55 degrees C (7). In the initial 8-12 animals tested, 5-7 recombinants were observed between Br and all loci except Dl7Mit39. Figure 1 Legend. Br maps to distal chromosome 17. (a) Haplotypes analysis of mice carrying recombination events in the D17Mit9 - Br region. Individual mice are designated BR(number), most are wild type because of the heavy loss of Br/+ animals before scoring. (b) The genetic map of distal Chr 17 showing the position of Br. Only 1 recombinant was found out of 8 backcross animals tested with D17Mit39, linkage between Br and D17Mit39 was confirmed by testing a further 40 animals and finding an additional 5 recombination events (x2=27, P<0.001). Subsequently, backcross progeny were scored for APVs at two other chromosome 17 loci, D17Mit9 and D17Mit41 (Fig. 1a). By minimising the number of double recombinants the order of loci was established as D17Mit9 Ð D17Mit39 Ð D17Mit41 - Br. Eight recombinants were found in the 38 mice scored for both D17Mit9 and D17Mit39, 5 recombinants were found in the 48 mice scored for both D17Mit39 and D17Mit41 and 1 recombinant was found in the 52 mice scored for both D17Mit41 and Br. Genetic distances (in cM) between loci were calculated as D17Mit9 - (21.0 +/- 6.6) Ð D17Mit39 - (10.4 +/- 4.4) Ð D17Mit41 - (1.9 +/- 1.8) - Br (Fig. lb). The order of the microsatellite loci and their genetic separation are consistent with those given in the 1997 chromosome 17 committee report and depicted in the Mouse Chromosome Atlas (5, 8). D17Mit39 was found to be variant between C3H/HeH and 101/H as well as between these two strains and Mus spretus. As Br arose in a C3H/HeH x 101/H Fl male, the mutant locus could be associated with either a C3H/HeH, or with a 101/H, chromosomal region. As the Br phenotype co-segregated with the C3H/HeH APV, i.e. all Br/+ backcross offspring were either C3H homozygotes or C3H/101 heterozygotes and no 101/H homozygotes were observed, we can conclude that the mutation arose on the C3H chromosome. In conclusion, Br maps distal to D17Mit41 in the telomeric region of mouse chromosome 17. This region contains several genes that lie in the 2p21 region on the human Chr 2 (9) and it is interesting to note that midline cleft syndrome (OMIM 15170) has also been mapped to 2p21 (10, 11). Therefore Br may be considered as a candidate homologue of midline cleft syndrome, or holoprosencephaly type 2, which is a dominant phenotype resulting from incomplete cleavage of the forebrain during early embryonic development. References 1. Searle, A.G. 1966. New mutants. Mouse News Letter 35:27. 2. Wenbin, M.A. and Lozanoff S. 1993. External craniofacial features, body size, and renal morphology in prenatal brachyrrhine mice. Teratology 47:321-332. 3. Lozanoff, S. 1993. Midfacial retrusion in adult brachyrrhine mice. Acta Anat. 147:125-132. 4. Lozanoff, S. 1994. Anterior base morphology in mice with midfacial retrusion. Cleft Palate-Craniofacial. Journal 31:417-428. 5. Lyon, M.F., Cocking, Y. and Gao, X. 1997. Mouse Chromosome Atlas, Mouse Genome 95:29-77. 6. Lyon, M.F., Rastan, S. and Brown, S.D.M. (ed.) 1996. "Genetic Strains and Variants of the Laboratory Mouse", Oxford University Press. 7. Blair, H.J. and Boyd, Y. 1994. Tfe3 maps close to Gata1 on the mouse X chromosome. Mouse Genome 92:511-512. 8. Hamvas, R. and Forejt, J. 1997. Committee Report for Mouse Chromosome 17 http://www.informatics.jax.org/. 9. Peters, J., Selley, R. and Cocking, Y. Mouse Gene List: http://www.mgu.mrc.ac.uk. 10. Hecht, B. K.-M, Hecht, F. and Munke M. 1991. Forebrain cleavage gene causing holoprosencephaly: deletion mapping to chromosome band 2p21. Am. J. Med. Genet. 40: 130. 11. Schell, U., Wienberg, J. et al. 1996. Molecular characterisation of breakpoints in patients with holoprosencephaly and definition of the HPE2 critical region 2p21. Hum. Mol. Genet. 5:223-229. |
