J Med Genet: first published as 10.1136/jmg.25.7.480 on 1 July 1988. Downloaded from Joalrn(ll of Medical Genetics 1988, 25, 480-487 Malformation syndromes: a review of mouse/human homology ROBIN M WINTER Fromii the Kennetivdy Galton Centre, Clinlicail Research Centre, Northiwick Park Hospital, Harrow, Middlesex HAI 3UJ. SUMMARY The purpose of this paper is to review the known and possible homologies between mouse and human multiple congenital anomaly syndromes. By identifying single gene defects causing similar developmental abnormalities in mouse and man, comparative gene mapping can be carried out, and if the loci in mouse and man are situated in homologous chromosome segments, further molecular studies can be performed to show that the loci are identical. This paper puts forward tentative homologies in the hope that some will be investigated and shown to be true homologies at the molecular level, thus providing mouse models for complex developmental syndromes. The mouse malformation syndromes are reviewed according to their major gene effects. X linked syndromes are reviewed separately because of the greater ease of establishing homology for these conditions. copyright. The purpose of this paper is to review the known even phenotypic similarity would be no guarantee and possible homologies between mouse and human that such genes in man and mouse are homologous". genetic malformation syndromes. Lalley and By identifying single gene defects causing similar following criteria for developmental abnormalities in mouse and man, McKusick' recommend the http://jmg.bmj.com/ identifying gene homologies between species: comparative gene mapping can be carried out, and if (1) Similar nucleotide or amino acid sequence. the loci in mouse and man are situated in homolo- (2) Similar immunological cross reaction. gous segments, further molecular studies can be (3) Formation of functional heteropolymeric performed to show that the loci are identical. Thus molecules in interspecific somatic cell hybrids this paper puts forward tentative homologies in the in cases of multimeric proteins. hope that some will be investigated and shown to be (4) Similar tissue distribution. true homologies at the molecular level. (5) Similar developmental time of appearance. Readers are referred to the comparative gene on September 26, 2021 by guest. Protected (6) Similar pleiotropic effects. maps of man and mouse3 for clues about possible (7) Identical subcellular locations. homologous chromosomal segments. The mouse (8) Similar substrate specificity. malformation syndromes are reviewed according to (9) Similar response to specific inhibitors. their major gene effects. X linked syndromes are (10) Cross hybridisation to the same molecular reviewed separately because of the greater ease of probe. establishing homology for these conditions. Where a Obviously, when one is considering homologies mouse mutant is included in Green's Genetic between genes causing developmental abnormalities, variants and strains of the laboratory mouse4 it is difficult to use many of these criteria which references are not given in this paper. Similarly, apply to protein or DNA sequences. One must human syndromes included in McKusick's Mendelian always bear in mind the point emphasised by inheritance in man5 are not referenced, but the Gruneberg2 that "identical genes on the genetic McKusick catalogue number is given in brackets. backgrounds of man and mouse would probably differ phenotypically from each other. Conversely, Methods Mouse mutants catalogued in standard reference " and reported individually in published Reccivcd for publicationi 18 Dccimbcr 1987. works4 Acceptcd for publicattion 29 D)ccmbcr 1987. reports were reviewed and compared with known 480 J Med Genet: first published as 10.1136/jmg.25.7.480 on 1 July 1988. Downloaded from Malformation syndromes: a review of mouselhuman homology 481 human malformation syndromes. The London Dys- the tail but with additional effects on the cranium to morphology Database7 was used to search for give an additional frontal bone. Hemizygotes and possible human homologies from over 1700 syn- female homozygotes apparently show cranioschisis dromes in the database. A database of all mouse and open neural tubes in utero, so there may be malformation mutants was also created and entries some relationship to the rare forms of X linked in the human and mouse databases were compared. neural tube defect seen in man (McK:30141). Homologies between mouse and human chromo- somal syndromes have been reported8 but these are MUTANTS AFFECTING SEGMENTATION AND not included in the present review. SCLEROTOME DIFFERENTIATION The sclerotome is the mass of cells in the somite that Neural tube defects and defects of will ultimately give rise to the vertebral cartilages. the axial skeleton The mutants that most closely parallel human conditions are pu-pudgy, Rf-rib fusion, and Mv- These can be divided into mutations that affect the malformed vertebrae. These three are models for development of the primitive streak or notochord, autosomal dominant or recessive forms of spondylo- those which affect neural tube development, and costal dysostosis in man (McK: 12260, 27730). those which affect segmentation and sclerotome Other mutants with somewhat similar effects are differentiation. There appears to be some difficulty Cd-crooked tail (which also manifests microphthal- in deciding whether the primary defect in some mia and small, absent, or non-erupted teeth in mouse mutants lies in the development of the neural homozygotes), rv-rib vertebrae, and rh-rachiterata. tube or in the primitive streak or notochord. The mutant am-amputated produces more severe defects including disorganisation of the vertebral MUTANTS AFFECTING PRIMITIVE STREAK OR column with absent lumbosacral vertebrae and rib NOTOCHORD DEVELOPMENT fusion, severely shortened limbs, and craniofacial These include Bt-bent tail, cy-crinkly tail, Lp-loop defects including cleft palate. There is thought to be copyright. tail, pr-porcine tail, Pt-pin tail, Sd-Danforth's short a basic defect of cell adhesion. It is possible that the tail, tc-truncate, T-t locus, Ts-tail short, and vt- Jarcho-Levin syndrome in man is homologous, but vestigial tail. Many of these result in a short tail in this is by no means certain because am has more the mouse, which is difficult to compare to man; severe limb defects. The syndrome described by however, several cause sacral agenesis and these Zimmer et all' is another possible homologue. may be interesting models. For example Sd- Dm-diminutive mice have malformed vertebrae Danforth's short tail mice have absent or short tails, and fused ribs as well as reduced blood islands http://jmg.bmj.com/ missing sacral vertebrae, and small or absent kid- leading to macrocytic anaemia. The anaemia shows neys. Homozygotes have anal atresia and sometimes similarities to that found in Fanconi (McK:22765) an absent rectum and bladder. There is similarity to and Diamond-Blackfan (McK:20590) syndromes in caudal regression in man (McK:26875). Another man. Flexed tail-f shows a similar association mutant, srn-siren, causes a similar phenotype to between vertebral abnormalities and anaemia. Tail sirenomelia in man. It complements, but is not kinks-tk causes abnormal vertebrae with the verte- allelic to, Sd. bral bodies ossifying from several centres and being on September 26, 2021 by guest. Protected The T locus, situated near the H-2 region on separated from the neural arches. Undulated-un is chromosome 17, is very complex and has been somewhat similar. extensively reviewed.9 Although it has been sug- The effects of some alleles at the dr-dreher locus gested as a model for neural tube defects in man, show similarities to the syndrome of conductive direct homology seems unlikely because absence or deafness, Klippel-Feil deformity, and vaginal atresia shortening of the tail is usually seen, sometimes with described by Park and Jones' (McK:14886). This sacral agenesis. Fellous et al"' described a large may be part of the MURCS spectrum. human pedigree segregating for various combina- tions of sacral agenesis, spina bifida aperta, and MUTANTS AFFECTING NEURAL TUBE spina bifida occulta. Segregation distortion was DEVELOPMENT seen, which is also a feature of the T locus in the These mutants include ct-curly tail, which gives mouse. In addition there was some evidence of spina bifida and cranial defects; alleles at the Fu linkage to PGM3 on chromosome 6. locus (fused, kinky, and knobbly) which is very close Lp-looptail mice do have forms of neural tube to the T locus; Sp-splotch which gives neural tube defect including enlarged cerebral ventricles in defects and a white belly spot and may be a defect of heterozygotes and craniorachischisis in homozy- the neural crest; and sst-shaker short tail, which gotes. Bn-bent tail is an X linked mutation affecting gives defects of the tail and spinal column, blebs in J Med Genet: first published as 10.1136/jmg.25.7.480 on 1 July 1988. Downloaded from 482 Robin M Winter the parietal region, as well as cerebellar abnor- ground. They are models for postaxial polydactyly malities and ataxia with inner ear deafness. The types A or B (McK:17420), or perhaps the rare mutant oel-open eyelids causes open eyelids at recessive types in man (McK:26345). In particular, birth, cleft palate, and sometimes cranioschisis. tu shows lack of penetrance, even in homozygotes, be Limb may expressed in heterozygotes occasionally, and defects there is evidence for modifying genes on the HEMIMELIAS (LUXATE, LUXOID MUTANTS) expression of the phenotype.' Thus it appears to These mutants usually cause tibial defects with pre- show great similarity to postaxial polydactyly type B axial polydactyly or absent preaxial toes. in man. Ed-extra digit is a further polydactyly Dh-dominant hemimelia, in heterozygotes, most mutant whose effects have not been fully described. often has absent toes, but preaxial polydactyly can also be present. The spleen is absent and the POLYDACTYLIES WITH OTHER ANOMALIES abdominal canal is shortened. The femur may be There are a number of complex mutants causing shortened and the pubic bones reduced.