sign in sign up
<<
Home , Apert syndrome, Cranioschisis, Cross syndrome, Fraser syndrome, Frontonasal dysplasia, Fryns syndrome

J Med Genet: first published as 10.1136/jmg.25.7.480 on 1 July 1988. Downloaded from

Joalrn(ll of 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 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 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 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. 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 The mutants that most closely parallel human conditions are pu-pudgy, Rf- fusion, and Mv- These can be divided into mutations that affect the malformed vertebrae. These three are models for development of the or notochord, autosomal dominant or recessive forms of spondylo- those which affect neural tube development, and costal 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 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 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, 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 . 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 ; 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 malities and ataxia with inner 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 , 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 may be There are a number of complex mutants causing shortened and the pubic bones reduced. Ribs, polydactyly and eye, , and renal defects that sternebrae, and presacral vertebrae may be absent. are associated with skin blebs during development. Hx-hemimelic extra toes has preaxial polydactyly of These include eb-eye blebs where polydactyly is all four feet with tibial and radial . associated with anophthalmia, hypoplastic or cystic Heterozygotes for lu-luxoid have preaxial polydactyly kidneys, , and clubbed feet; fh-fetal of the hindfeet and homozygotes have, in addition, haematoma and heb-head bleb where polydactyly is preaxial polydactyly of the forefeet as well as in- associated with cloudy corneae or absent eyes; and creased presacral vertebrae, ribs, and sternebrae. my-blebs associated with brain abnormalities, renal lx-luxate heterozygotes show preaxial abnormalities agenesis, hydronephrosis, exomphalos, and syn- together with horseshoe and hydronephrosis. . A further mutant bl-blebbed resembles my Heterozygotes for 1st-Strong's luxoid have preaxial but does not manifest polydactyly. Some of these

polydactyly of the hindfeet, whereas homozygotes mutants resemble Meckel (McK:24900) or perhapscopyright. have more severe abnormalities of all four limbs. hydrolethalus (McK:23660) syndromes in man, Some of these mutants are models for Werner particularly eb. It is of interest that my and bl, which mesomelia in man (McK:18877), particularly Hx, are not syntenic, resemble one another and Fraser lu, and 1st. There are similarities to tibial agenesis syndrome (McK:21900). This sug- with mirror foot (McK:13575), Majewski syndrome gests a possible aetiology and possible genetic (McK:26352), and Mohr-Majewski compound.13 heterogeneity in . Wiedemann et al14 described a male with tibial Hop-sterile (hop) and hydrocephalic-polydactyly http://jmg.bmj.com/ agenesis (unilateral), preaxial polydactyly of the (hophPY) are allelic and cause preaxial polydactyly of toes, other skeletal anomalies, and hydroureter who fore and hindfeet, (in hophPY), and seems to resemble lx. male sterility owing to abnormalities of sperm tails. Direct homologues are difficult to identify but there OTHER POLYDACTYLIES are similarities to hydrolethalus (McK:23660) and Xt-extra toes manifests in heterozygotes with pre- acrocallosal (McK:10105) syndromes. axial polydactyly of the fore and hindfeet with Fidget-fi combines preaxial polydactyly of the on September 26, 2021 by guest. Protected occasional postaxial polydactyly (represented by a hind limb often with an extra triphalangeal digit, rudimentary digit). Some alleles cause an interfrontal small eyes with absence of the lacrimal glands, bone. This locus seems to be directly homologous to dislocated , and inner ear abnormalities. There Greig syndrome in man (McK: 17570), particularly as are some similarities to the lacrimo-auriculo-dento- the loci are closely linked to TCRG in both species. digital syndrome (McK:14973). Pdn-polydactyly Nagoya'5 is a similar mutant which Ds-disorganisation is an extremely interesting has not been tested for allelism with Xt. mutation. In heterozygotes it causes almost doub- Ps-polysyndactyly in heterozygotes causes syn- ling of the digits, usually on one limb only, additional dactyly, particularly of the first and second toes in limbs close to normal limbs, limb-like projections on the hindfoot, and an extra digit between digits 3 and the ventral abdomen, and papillae resembling 4 with occasional postaxial polydactyly of the urogenital papillae or extra limbs almost anywhere forefeet. This mutant seems to be homologous to on the body. Half the affected mice have cranial syndactyly type II () in man abnormalities. The author knows of one patient (McK: 18600). submitted to the London Dysmorphology Database Po-postaxial polydactyly and tu-toe ulnar are with similar features (patient of Dr Dian Donnai). mutants which give rise to postaxial polydactyly in The child had nine toes on one foot with hypoplasia varying frequency according to the genetic back- of the leg and a toe-like structure on the abdomen. 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 483 Ts-tail short causes tail abnormalities (see above) Hd-hypodactyly causes absence of the terminal as well as vertebral fusion, asymmetry of the length phalanx or complete hallux in heterozygotes and a of the humerus and femur, and a triphalangeal first single digit on all four feet in homozygotes. Homo- digit on the forefoot. There is prenatal anaemia logies are not immediately obvious, but Miura'8 owing to reduced blood islands in the yoke sac. described a mother and daughter with absent There seem to be similarities to Aase-Smith syn- halluces and . drome (McK:20560). -ol produces reduction of the post- axial digits, fusion of ribs, small spleen, and absent SYN DACTYLIES or horseshoe kidneys. Weyers19 pointed out that it is Isolated syndactyly in the mouse mainly involves directly homologous to a human mutation he digits 2 to 4. jt-joined toes is a recessive mutant described (McK: 19360). causing soft tissue syndactyly. sm-syndactylism is another Postaxial hemimelia-px causes absence of the recessive causing soft tissue fusion in the digits on the ulna side of the limb with a reduced forefeet and bony fusion in the hindfeet, sometimes ulna, Mullerian defects, and an oval foramen in the involving digit 1. These mutants are models for the scapula. It seems to be similar to the autosomal human forms of isolated syndactyly, although these dominant syndromes described by Schinzel (McK: are usually dominant. A further mutant, Dsy- 18145) or Halal.21' dominant syndactylism has been reported that -pc causes mesomelic shortening of appears to be very similar to syndactyly type I in the limbs with syndactyly and preaxial polydactyly. man (McK:18590). Extra centres of cartilage formation are seen (tarsus, Hm- is a dominant mutation that deltoid crest of humerus, and on each side of the causes syndactyly of digits 2 to 5 with flexion at the nasal capsule). The head is elongated and a cleft proximal interphalangeal joints. This form of syn- palate, micrognathia, and hypoplastic maxilla and dactylism resembles that seen in premaxilla can be seen. There are similarities to (McK:10120) and the very rare syndactyly type IV Roberts syndrome (McK:26830), although this is copyright. (McK: 18620). said to be associated with a prominent premaxilla in Limb deformity-ld is a recessive that causes cases where clefting is not complete fusion present. of the radius and ulna and tibia and Dac-dactylaplasia causes a malformation which is fibula. The bones of the hands and feet are very similar to autosomal dominant split hand and disorganised and fused. Small or absent kidneys may foot be found. The limb malformations appear very in man (McK:18360). It is of interest that similar manifestation of the gene may be controlled by http://jmg.bmj.com/ to the Cenani-Lenz syndrome in man another recessive locus, thus possibly explaining the (McK:21278), which is also recessive. extreme variation of penetrance.21 Shaker-with-syndactylism-sy causes skin or bony to 4 on all four limbs and Ul-ulnaless causes severe reduction of the radius fusion between digits 2 and ulna as well as of the tibia and fibula. It is between the carpals and tarsals. The mice are deaf similar to some forms of and have head tossing and circling owing to inner mesomelia in man, perhaps ear abnormalities. A direct human is the Langer (McK:24970), Nievergelt (McK:16340), homologue or Reinhardt-Pfeiffer (McK: 19140) types. A reces- difficult to identify. on September 26, 2021 by guest. Protected Os-oligosyndactylism causes syndactyly between sive mutant causing shortening of the radius and digits 2 and 3 (sometimes 4) on all four limbs and ulna is fl-flipper . reduction of the preaxial border of the limbs. Hypoplastic kidneys, leading to insipidus, Bone dysplasias are a feature. Sig-sightless mice have hydrocephalus and syndactyly of the hindfeet, most severe in OSTEOPETROSES homozygotes. Again direct homologues are difficult Four mutants cause in the mouse; to identify, but Os shows similarities to some of the these are gl-grey lethal, mi-, oc- acrorenal syndromes in man (McK:10252) and also osteosclerotic, and op-osteopetrosis. Reversal of Sorsby syndrome osteopetrosis can be brought about by transplantation (McK:12040). of marrow or spleen cells in gl and mi, suggesting a OTHER ABNORMALITIES OF THE LIMBS defect of osteoclasts or other stem cells. Grey lethal Brachypodism-bp causes hypoplasia of the middle is a good model for autosomal recessive osteopetrosis and proximal phalanges, carpal and tarsal fusions, in man (McK:25970). There are several alleles at the and shortening of the limbs. In the mouse it is mi locus, some semi-dominant. Because of the autosomal recessive; a somewhat similar mutant in microphthalmia and dental abnormalities, there are man, Osebold-Remondini syndrome,'7 is autosomal similarities to oculo-dento-digital syndrome (McK: dominant. 16420); some alleles cause , sug- J Med Genet: first published as 10.1136/jmg.25.7.480 on 1 July 1988. Downloaded from

484 Robin M Winter gesting similarities to Cross syndrome (McK:25780). condition was asymmetrical and resembled hemi- Osteopetrotic mice (op) do not respond to marrow facial microsomia (McK:14140). transplantation and the disorder resolves with age. Phocomelia-pc has been mentioned when con- sidering limb defects. Homozygotes have a wide cleft palate, absent nasal bones, and reduced maxilla The precise homology between mouse and human and premaxilla. Two mutants, Dc-dancer and Tw- chondrodysplasias is difficult to assess. Certainly twirler, cause cleft lip and palate together with mutants with similar names, such as , abnormalities of the inner ear. Two separate mutants are not necessarily homologous. The following are extremely similar to agnathia- appear to be true chondrodysplasias: bm-brachy- in man (McK:20265); these are j-jaw lethal and oto- morphic, can-cartilage anomaly, cho-chondro- otocephaly. The mutant se-short ear causes reduction dystrophy, cmd-cartilage matrix deficiency, cn- in size of the ear, reduction in body size, reduction achondroplasia, de-droopy ear, Dmm-dispropor- or absence of many small bones or bony processes, tionate micromelia, Dre-dominant reduced ear, hydronephrosis, and diaphragmatic defects. There hcp-, pad-paddle, sho-short head, are some similarities to (McK: slm-short limbed mutant, smc-spondylometaphyseal 22985). chondrodysplasia, stb-stubby, stm-stumpy. These mutants result in shortening of the limbs and trunk, CLEFT PALATE sometimes with a shortened, domed skull and a cleft As mentioned above, a number of chondrody- palate. Cartilage matrix deficiency-cmd resembles strophies in the mouse are associated with cleft achondrogenesis type II, but there are radiological palate. These include cho, cmd, cn, pad, and stb. and morphological differences between the two Muscular dysgenesis-mdg causes abnormal develop- which led Eteson et at22 to consider that they are not ment and degeneration of the skeletal muscles. A homologous. It is interesting that most chondro- small and cleft palate are thought to be dystrophies in the mouse are recessive, whereas in secondary phenomena. A number of inbred strainscopyright. man many are dominant. This does not necessarily of mice are also susceptible to cleft palate, both mean that some of the recessive mutants in the spontaneously and in response to environmental mouse cannot be homologous to dominant mutants agents, which may throw light on the cause of the in man; however there do seem to be difficulties isolated defect in man.27 in comparing morphological and histological 2 23 EYE ABNORMALITIES

features. http://jmg.bmj.com/ A mouse homologue for cleidocranial dysplasia Several genes in the mouse cause cataracts. These (McK: 11960) has recently been reported. It has are reviewed by Muggleton-Harris.28 In some there been given the provisional gene symbol Ccd.24 may be abnormalities of one of the crystallin genes. A mouse mutant that may be homologous to a Two loci in the mouse cause severe microphthalmia severe form of osteogenesis imperfecta (McK: or anophthalmia without other major defects. These 25940) has been described. This is fro-fragilitas are ey-1. and ey-2 (eyeless-1 and -2). They are ossium. 2 models for recessive anophthalmia in man (McK:

20690). on September 26, 2021 by guest. Protected Craniofacial abnormalities Cm- and Dey-Dickies small eye cause forms of colobomatous microphthalmos which are FACIAL ABNORMALITIES models for forms of microphthalmos in man. The A number of mutants cause clefting of the mid-face. mutant dyl-dysgenetic lens appears to cause a form These are Ph-patch, Ts-tail short, and Xt-extra toes of Peters' anomaly. (in homozygotes). Both Ph and Xt have a central face bleb at 13 days' gestation as well as a white belly Miscellaneous mutants spot. The latter may indicate a neural crest abnor- mality. Dominant has been Three mutants in the mouse have similarities to described in man (McK:13676). in man (McK:19350, The mutant far-first arch defect affects palate 19351, 27758) because they manifest with combi- closure and the development of structures arising nations of , sensorineural deafness, and from the first branchial arch. There are similarities aganglionic megacolon. They are Dom-dominant to human first and second branchial arch syn- megacolon, ls-lethal spotting, and s-piebald (there dromes. Juriloff et at26 showed that the gene was are several alleles at this locus). The existence of recessive on some genetic backgrounds, but domi- different loci is of interest because of the evidence nant on other backgrounds. In the latter case the for heterogeneity of Waardenburg syndrome in man 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 485

TABLE Human multiple malformation syndromes with Watardcnburg syndromc Is-leth ii spottitig possible mouse Waardenburg syndrome s-pichild etc models. Watardenburg syndrome Vat-vatritint waddler Walker-Wairburg or Meckel-Gruber bh-brtlin hcrnitt Human coniditioni Possible mouise miodiel syndrome Werner mesomelia 1st-Stron 's luxoid Aarskog syndrome Bhd-broad headed Weyers oligodactyly ol-oligod tctvlv Aase-Smith syndrome Ts-tatil short Wiedemann et al"4 Ix-luxatte Acrorenal syndromes Os-oligosyndactylism X linked anhidrotic ectodermal dvsplaisia Tta-tabh Agnathia-holoprosencephaly j-jaw lethal X linked chondrodysplaisia punctatal Bpat-barc p itches Agnathia-holoprosencephaly oto-otoccphally X linked hypophosphataiemic rickets Hvp-hvpophosphattaemia Ataxia telangiectasia wst-wasted X linked ichthyosis with hypogonadism sf-scurfv Anophthalmia, autosomal recessive ev- .2-eveless- and 2 X linked neural tube defects Bn-bent ttil Caudal regression Sd-Danforth's short tail Cenani-Lenz syndrome Id-limb deformitv Chediak-Higashi svndrome bg-beige Cleidocranial dysplasia Ccd-cleidocrzanial dvsplalsia Cross syndrome mi-microphthalmia Ectodermal dysplasia cr-crinkled Ectodermal dysplasia dI-downless (two possible dominant types and a recessive form). Eetodermal dysplasia Sik-sleek Searle29 has also suggested that Va-varitint waddler Fabry disease Ags-alpha galactosidase Fraser syndrome bI-biebbed might also be a homologue. Fraser syndrome niv-blebs The mutant bg-beige shows pigment dilution and Fryns syndrome sc-short cear Greig cephalopolysyndactyly Xt-extrat toes defective chemotaxis of granulocytes. It is thought Greig eephalopolysyndactvly Pdn-polvdactvly Nagoya to be homologous to Chediak-Higashi syndrome Halal2" px-postaxial hemimeliai Hemifacial microsomia fair-first arch malformation (McK:21450).3 Pale ear-ep has diluted pigmenta- Hermansky-Pudlack syndrome ep-pale ear tion of the extremities and a platelet storage pool Hydrolethalus; aerocallosal svndrome hop-hop sterilc deficiency. Homology to Hermansky-Pudlak (McK: Jarcho-Levin: Zimmer1 arm-amputated Klippel-Feil syndrome with Muillerian dr-dreher 20330) syndrome has been suggested.3' aplasia Two mouse mutants have interesting effects that Lacrimo-auriculo-dento-digital fi-fidget copyright. Lenz microphthalmia Ie-eve-eiar reduction resemble restrictive dermopathy or cocoon in Lesch-Nyhan syndrome Hprt-hypoxainthine phosphoribosyl man.32 33 These are pf-pupoid fetus and Er-repeated transferase Meckel syndrome eb-eye blebs epilation. In both these mutants there is thickening Menkes syndrome Mo-mottled etc of the epidermis with shortening of the limbs and tail Mierophthalmia with coloboma Cm-colobomai as well as syndactyly. Microphthalmia with coloboma Dev-Dickies small eye Hd-hypodaictvly Mutations at several loci cause forms of MURCS association dr-dreher ectodermal dysplasia. These include cr-crinkled, dl- http://jmg.bmj.com/ Neural tube defeet Fu-fused Neural tube defeet Sp-splotch downless, and Dlslk_sleek. A mouse homologue of Neural tube defect Lp-loop tal ataxia telangiectasia (McK:20890) has been re- Neural tube defect T-t locus Neural tube defect ct-curly tail ported; this is wst-wasted.34 However, other studies Nievergelt; Reinhardt-Pfeiffer svndrome Ul-ulnaless have given conflicting results.35 Two mutants cause Ornithine transcarbamylase deficiency spf-sparse fur situs These are iv- Orofaciodigital syndrome type I Xpl-X linked polvdactyly complete inversus (McK:27010). Osebold-Remondini bp-brachypodism situs inversus viscerum and vi-visceral inversion. Osteogenesis imperfecta type 11 fro-fragilitais ossium Osteopetrosis. severe autosomal gI-grey lethal recessive form X linked loci on September 26, 2021 by guest. Protected Pelizaeus-Merzbacher syndrome ip-jimpy Peters' anomaly dyl-dysgcnetic lens Postaxial polvdactyly type A Po-postatxiall polydaictyly There are several well recognised X linked loci in Postaxial polydactyly type B tu-toe ulnair the mouse that are homologous to human condi- Restrictive dermopathy Er-repcated cpilation Restrictive dermopathy pf-pupoid fetus tions. These include Ags-alpha galactosidase (Fabry), Roberts syndrome pc-phocomclic Bpa-bare patches (X linked chondrodysplasia punc- Schinzel px-postaxial hemimelia tata),36 Hprt-hypoxanthine phosporibosyl transferase Sirenomelia srn-siren Situs inversus iv-situs inversus viscerum (Lesch-Nyhan syndrome), Hyp-hypophosphataemia Situs inversus vi-visceral inversion (hypophosphataemic rickets), jp-jimpy (Pelizaeus- Split hand/foot Dac-dactylaiplaisia Spondylocostal dysostosis Mv-malformed vertcbrae Merzbacher disease), Mo-mottled (Menkes' disease), Spondylocostal dysostosis Rf-rib fusion spf-sparse fur (OTC deficiency), Sts-steroid sulpha- Spondylocostal dysostosis rv-rib vcrtebrate tase Spondylocostal dysostosis rh-rachiterata (equivalent to the human enzyme), Ta-tabby Spondylocostal dysostosis pu-pudgy (hypohidrotic ectodermal dysplasia), and xid-X Steroid sulphatase deficiency Sts-steroid sulphatase linked immune deficiency (Bruton's disease). Syndactyly type I Dsv-dominaint syndactylism Syndactyly type I jt-joined toes Note that, as pointed out by Buckle et al,37 sf- Syndactyly type 11 (synpolydaictyly) Ps-polysyndactyly scurfy may be homologous to X linked ichthyosis Syndactyly type IV; Apert syndrome Hm-hammer toe Testicular feminisation Tfm-testicular feminisaition with hypogonadism and is a separate locus from Sts- Waardenburg syndrome Dom-dominant megacolon steroid sulphatase. In man anosmia, ichthyosis, J Med Genet: first published as 10.1136/jmg.25.7.480 on 1 July 1988. Downloaded from

486 Robin M Winter

hypogonadism, and neurological abnormalities have References been reported with steroid sulphatase deficiency,38 Lalley PA, McKusick VA. Report of the committee on whereas ichthyosis and hypogonadism without steroid comparative mapping. HGM8. Cytogenet Cell Genet 1985;40: 536-66. sulphatase deficiency has also been reported.39 2 Gruneberg H. Brachypodism in the mouse. Birth Defects A number of other X linked loci have possible 1971 ;XIII(1):221-30. homology. One of the more compelling candidates 3 Searle AG, Peters J, Lyon MF, Evans EP, Edwards JH, Buckle is Bhd-broad headed; this locus is within 1 cM of Ta VJ. Chromosome maps of man and mouse III. Genomics 1987;1:3-18. and manifests with a broad head and nose in 4 Green MC, ed. Genetic variants and strainis of the laboratory heterozygotes with similar features and early lethality mouse. Berlin: Gustav Fisher Verlag, 1981. in males. Comparison of the abnormalities and of McKusick VA. Mendelian inheritanice in mnan. 7th ed. Balti- the mouse and human gene maps suggest that Bhd more: Johns Hopkins University Press, 1986. 6 Johnson DR. The genetics of the skeleton. Oxford: Clarendon may be homologous to Aarskog syndrome (McK: Press, 1986. 30540). 7 Winter RM, Clark RD, Ashley K, Gibbs G. A combinatorial Ie-eye-ear reduction causes anophthalmia in method for grouping cases with multiple malformations. J Med hemizygotes, together with a small, thickened exter- Genet 1988;25:118-21. 8 Reeves RH, Gearhart JD, Littlefield JW. Genetic basis for a nal ear. There are some similarities to Lenz micro- mouse model of Down syndrome. Brain Res Bull 1986;16: phthalmia, particularly the family described by 803-14. Goldberg and McKusick.4" Klein J, Hammerberg C. The control of differentiation by the T It-irregular teeth manifests with absent or reduced complex. Immunol Rev 1977;33:70-104. Fellous M, Boue J, Malbrunot C, et al. A five-generation family upper and lower incisors. Hemizygote males die with sacral agenesis and spina bifida: possible similarities with before birth and in view of this, and the teeth the mouse T-locus. Am J Med Genet 1982;12:465-87. abnormalities, (McK:30830) Zimmer EZ, Taub E, Sova Y, et al. Tetra- with multiple may be a candidate for homology. malformations in six male of one kindred. Eur J Pediatr 1985;144:412-4. Xpl-X linked polydactyly is an X linked dominant 12 Park IJ, Jones HW Jr. A new syndrome in two unrelated mutation causing varying degrees of preaxial poly- females: Klippel-Feil deformity, conductive deafness and absentcopyright. dactyly of the hindfoot and urogenital anomalies . Birth Defects 1971 ;8(6):31 1-7. (hydroureter, hydronephrosis, cystic or missing 3 Baraitser M, Burn J, Fixsen J. A female with features of Mohr and Majewski syndromes: variable expression, a genetic kidneys). The mutation appears to be fully domi- compound, or a distinct entity. J Med Genet 1983;20:65-7. nant and hemizygous males are viable but sterile 14 Wiedemann HR, Grosse KR, Dibbern H. An atlas of character- owing to undescended testes. It is difficult to find a istic syndromes: a visual aid to diagnosis. London: Wolfe this mutant. Orofacio- Medical, 1985:296-7. direct human homologue for http://jmg.bmj.com/ Hayasaka 1, Nakatsuka T, Fujii T, Naruse I. Polydactyly digital syndrome type 1 (McK:31120) shares some Nagoya Pdn: a new mutant gene in the mouse. Exp Animals common features, but is lethal in utero in human 1980;29:391-5. hemizygotes. The only other X linked polydactyly lb Center EM. Postaxial polydactyly in the mouse. J Hered syndromes in man are Golabi-Rosen syndrome 1951 ;46:144-8. '7 Osebold WR, Remondini DJ, Lester EL, et al. An autosomal (McK:30605) and Simpson-Behmel syndrome dominant syndrome of with mesomelic shortness of (McK:31287) which both have postaxial polydacyly limbs, abnormal carpal and tarsal bones, hypoplastic middle (and which may indeed be the same condition). phalanges and bipartite calcanei. Am J Med Genet 1985;22: 791-809. Td-tattered causes areas of scarring of the skin on September 26, 2021 by guest. Protected 18 Miura T. Congenital familial hypoplastic associated with with patchy alopecia in female heterozygotes. It is a of the toe. J Hand Surg 1984;9:42t-2. prenatal lethal in hemizygote males. Direct homology 9 Weyers H. Das oligodactylie-syndrom des mensehen und seine is difficult to find but there may be similarities to parallelmutation bei der hausmaus. Ann Pediatr (Paris) 1957; Goltz syndrome (McK:30560). 189:351-70. 2(0 Halal F. A new syndrome of severe upper limb hypoplasia and Mullerian duct anomalies. Am J Med Genet 1986;24:119-26. Conclusions 21 Chai CK. Dactylaplasia in mice: a two-locus model for develop- mental anomalies. J Hered 1981;72:234-7. In the present paper over 80 malformation syn- 22 Eteson DJ, Sillence DO, Lachman RS, Rimoin DL. The mouse skeletal mutants: models for the human skeletal dysplasias. In: dromes with possible mouse/human homology are Normal and abnormal bone growth: basic and clinical research. reviewed. Some of the suggested homologies are New York: Alan R Liss, 1985:141-51. very tentative and all require further study. The 23 Rimoin DL. The chrondrodystrophies. Adv Hum Genet 1975;5: table summarises the possible homologies men- 10-118. tioned in the text. 24 Sillence DO, Ritchie HE, Selby PB. Skeletal anomalies in mice with cleodocranial dysplasia. Am J Med Genet 1987;27:75-85. 25 Guenet JL, Stanescu R, Maroteaux P, Stanescu V. Fragilitas The author would like to thank Drs A G Searle and ossium: a new autosomal recessive mutation in the mouse. J D R Johnson for helpful comments on the manu- Hered 1981;72:440-1. script. 26 Juriloff DM, Harris MJ, Froster-Iskenius U. Hemifacial de- 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 487

ficicncy induced by a shift in of the mouse mutation 35 Personal communication. Mouse News Letter 1984;70:78-80. far: a possible genetic model for hemifacial microsomia. 36 Happel R, Phiips RJS. Roessner A, Junemann G. Homologous J Craniiofac Getnet Dev Biol 1987;7:27-44. genes for X-linked chondrodysplasia punctata in man and 27 Slavkin HC. Congenital craniofacial malformations: issues and mouse. Hum Genet 1983;63:24-7. perspectives. J Prosthet Detnt 1984;51:109-18. 37 Buckle VJ, Edwards JH, Evans EP, et al. Comparative maps of 28 Muggleton-Harris AL. Mouse mutants: model systems to study human and mouse X chromosomes. Cytogenet Cell Genet congenital cataract. Int Rev Cytol 1986;104:25-36. 1985;40:594-5. 29 Searle AG. Comparative getnetics of coat colour in mammals. .3x Sunohara N. Sakuragawa N, Satoyoshi E, et al. A new syndrome New York: Logos Press, 1969. of anosmia, ichthyosis, hypogonadism, and various neurological 3" Oliver C, Essner E. Distribution of anomalous lysosomes in the manifestations with deficiency of steroid sulfatase and arylsulfa- beige mouse: a homologue of Chediak-Higashi syndrome. tase C. Ann Neurol 1986;19:174-81. J Histochem Cytochemn 1973;21:218-28. 39 Traupe H, Muller-Migl CR, Kolde G, et al. Ichthyosis vulgaris 3' Novak EK, Hui SW, Swank RT. The mouse pale ear pigment with hypogenitalism and hypogonadism: evidence for different mutant as a possible animal model for human platelet storage genotypes by lipoprotein electrophoresis and steroid sulphatase pool deficiency. Blood 1980;57:38-43. testing. Clin Genet 1984;25:42-51. 32 Stevenson RE, Saul RA. Collins J, Davis WM, Lanford C. 4 Goldberg MF, McKusick VA. X-linked colobomatous micro- Cocoon fetus-fetal encasement secondary to ectodermal dys- phthalmos and other congenital anomalies. A disorder re- plasia. Proc Greenwood Genet Center 1987;6:10-15. sembling Lenz's dysmorphogenetic syndrome. Am J Ophthalmol 33 Toriello HV. Invited editorial comment. Restrictive der- 1971;71:1128-33. mopathy and report of another case. Am J Med Genet 1986;24:625-9. Correspondence and requests for reprints to Dr R M -4 Schultz LD, Sweet HO, Davisson MT. Coman DR. 'Wasted', a Winter, Kennedy Galton Centre, Clinical Research new mutant of the mouse with abnormalities characteristic of Centre, Northwick Park Hospital, Watford Road, ataxia telangiectasia. Nature 1982;297:402-4. Harrow, Middlesex HAl 3UJ. copyright. http://jmg.bmj.com/ on September 26, 2021 by guest. Protected