RESUMEN
Genetic mapping and the examination of "candidate genes" for isolating loci associated with clinical syndromes can be greatly accelerated if there is information about where in the genome a particular locus might be situated. Such clues can come from homology to mouse mutants that have been mapped and knowledge of homology between mouse and human chromosomal segments. Further clues can come from chromosome aberrations giving a similar phenotype. However, these clues are often scattered widely in published reports, and even if they are collected together in catalogues or databases there is no rapid way of moving from one data type to another. The Dysmorphic Human and Mouse Homology Database (DHMHD) is designed to ease this data transition. DHMHD comprises detailed information from four separate sources and enables cross referencing through phenotypic and chromosome homology. The DHMHD system is a prototype which is now available online through the World-Wide Web.
Asunto(s)
Mapeo Cromosómico , Redes de Comunicación de Computadores , Bases de Datos Factuales , Animales , Genotipo , Humanos , Ratones , Fenotipo , Homología de Secuencia de Ácido NucleicoRESUMEN
Details are given of 214 loci known to be associated with human hereditary disease, which have been mapped on both human and mouse chromosomes. Forty two of these have pathological variants in both species; in general the mouse variants are similar in their effects to the corresponding human ones, but exceptions include the Dmd/DMD and Hprt/HPRT mutations which cause little, if any, harm in mice. Possible reasons for phenotypic differences are discussed. In most pathological variants the gene product seems to be absent or greatly reduced in both species. The extensive data on conserved segments between human and mouse chromosomes are used to predict locations in the mouse of over 50 loci of medical interest which are mapped so far only on human chromosomes. In about 80% of these a fairly confident prediction can be made. Some likely homologies between mapped mouse loci and unmapped human ones are also given. Sixty six human and mouse proto-oncogene and growth factor gene homologies are also listed; those of confirmed location are all in known conserved segments. A survey of 18 mapped human disease loci and chromosome regions in which the manifestation or severity of pathological effects is thought to be the result of genomic imprinting shows that most of the homologous regions in the mouse are also associated with imprinting, especially those with homologues on human chromosomes 11p and 15q. Useful methods of accelerating the production of mouse models of human hereditary disease include (1) use of a supermutagen, such as ethylnitrosourea (ENU), (2) targeted mutagenesis involving ES cells, and (3) use of gene transfer techniques, with production of 'knockout mutations'.
Asunto(s)
Enfermedades Genéticas Congénitas/genética , Animales , Mapeo Cromosómico , Variación Genética , Humanos , Ratones , Proto-Oncogenes Mas , Proto-Oncogenes , Especificidad de la EspecieRESUMEN
A complex murine chromosomal rearrangement, T(In1;5)44H, was recovered after 5 Gy + 5 Gy (given 24 h apart) spermatogonial X-irradiation. T44H is a paracentric inversion of most of Chromosome (Chr) 1 (1A1-1H6), followed by splitting of the inverted segment through a reciprocal translocation with Chr 5, the latter breakpoints being in 1C2 and 5F. Linkage tests have shown that the probable order on Chr 1 is fz-ln-T44H with 2.4 +/- 2.4 crossover units between ln and T44H. On Chr 5 the probable order is W-T44H-go-bf with 7.1 +/- 4.9 crossover units between T44H and go. All heterozygotes show a marked dilution of coat colour. Heterozygotes of both sexes are fertile, producing small litters with a marked shortage of T44H carriers. The number of live embryos produced from female carriers is significantly lower than from males. Despite the complex nature of the rearrangement, complete chromosome pairing and chiasma formation occur regularly at meiosis. Depending on the strands involved, this leads to the production of either one or two dicentric chromatids per spermatocyte, and their disjunctional fate can be followed into metaphase II. Analysis of chromatid classes at this stage suggests reasons for both the high embryonic mortality and the shortage of liveborn T44H carriers.
Asunto(s)
Aberraciones Cromosómicas/genética , Trastornos de los Cromosomas , Ratones/genética , Espermatozoides/efectos de la radiación , Animales , Inversión Cromosómica , Femenino , Ligamiento Genético , Heterocigoto , Infertilidad Femenina/etiología , Cariotipificación , Tamaño de la Camada , Masculino , Meiosis , Fenotipo , Translocación GenéticaRESUMEN
In order to develop mouse models for human mutagen-sensitive syndromes, we carried out cytogenetic characterization of several mouse mutants and MS/Ae mice showing enhanced radiosensitivities. The applied cytogenetic techniques include chromosomal analysis of in vitro cell cultures and lymphocyte cultures as well as in vivo UDS in hepatocytes, induction of micronuclei in polychromatic erythrocytes and translocation induction in spermatogonial stem cells. Among the mutations studied, namely the contrasted allele of steel (Slcon), viable dominant spotting (Wc), wasted (wst), varitint-waddler (Va) and dystonia musculorum (dt) as well as MS/Ae mice, various iso-, hyper- or hypo-sensitive conditions were recorded. Only Va and dt appear to be associated with some deficiency in DNA repair.
Asunto(s)
Ratones Mutantes , Tolerancia a Radiación/genética , Animales , Médula Ósea/efectos de la radiación , Células de la Médula Ósea , Células Cultivadas , Aberraciones Cromosómicas , Cromosomas/efectos de la radiación , ADN/biosíntesis , Femenino , Genotipo , Hígado/citología , Hígado/metabolismo , Hígado/efectos de la radiación , Masculino , Ratones , Testículo/citología , Testículo/efectos de la radiaciónRESUMEN
Four male-fertile translocations, T(2;4)13H, T(2.8)26H, T(7;18)50H and T(1;13)70H were crossed to the inbred strains CBA/H and C57BL/6J. F1 heterozygotes were compared with wild-type litter-mates for signs of spermatogenic impairment, in view of previous reports that the C57BL strain had this effect in the T(14;15)6Ca translocation. There was a general tendency for body-weights to be slightly reduced in translocation carriers vs. wild-type. Mean testis weights were significantly reduced on the C57BL background with all four translocations as compared to wild-type, but also significantly increased in T26H on CBA. Sperm counts were also reduced on the C57BL background in T13H, T50H and T70H (significantly so in the last two) but were significantly increased in T13H on a CBA background. Only in T50H did the frequency of sperm-head abnormalities show any marked change in the translocation heterozygotes, being approximately doubled with both CBA and C57BL backgrounds although still remaining at a low level. It was concluded that the deleterious effects of C57BL strains on spermatogenesis in translocation heterozygotes were not confined to T6Ca but were probably widespread. Some inconclusive evidence suggested that this might be because some genetic factors associated with C57BL tended to reduce chiasma frequencies in translocation heterozygotes.
Asunto(s)
Infertilidad Masculina/genética , Espermatogénesis/genética , Translocación Genética/genética , Animales , Peso Corporal , Cruzamientos Genéticos , Heterocigoto , Tamaño de la Camada , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos CBA , Cromosomas en Anillo , Recuento de Espermatozoides , Cabeza del Espermatozoide/patología , TestículoRESUMEN
A new murine tester stock for primary nondisjunction incorporates three genetically marked Robertsonian translocations with tribrachial homology (TBH): Rb(6.15)1Ald, Rb(4.6)2Bnr, and Rb(4.15)4Rma. The resultant tricentromeric meiotic configuration leads to 100% aneuploid gametes, but the TBH stock can be maintained by intercrossing, through the complementation of nullisomic and disomic gametes. The only neonatal survivors from tescrosses to wild type come from complementation of aneuploid gametes and genetic tests allow wild type gains or losses of Chromosomes 4, 6, and 15 to be distinguished. Alternatively, cytogenetic examination allows products of wild type chromosome gain, with one metacentric, to be separated from chromosome loss with two metacentrics. A pilot study, with 0-2 Gy X-irradiation of oocytes at diakinesis, revealed twelve examples of chromosome loss in wild type gametes but none of chromosome gain and thus provided no evidence for the induction of nondisjunction.
Asunto(s)
Aneuploidia , No Disyunción Genética , Animales , Animales Recién Nacidos , Bandeo Cromosómico , Cruzamientos Genéticos , Femenino , Prueba de Complementación Genética , Masculino , Meiosis , Ratones , Homología de Secuencia de Ácido Nucleico , Translocación GenéticaRESUMEN
Heterozygotes for the reciprocal translocation T(7;15)9H were intercrossed, with albino (c) and underwhite (uw) as genetic markers, in order to study genetic complementation in mouse chromosome 7. Chromosome 15 is known to show normal complementation. Neither reciprocal cross in which one parent was c/c and the other wild type yielded albino progeny at birth although about 17% would be expected, but albino foetuses were recovered when the mother was c/c and father wild type. These products of maternal duplication/paternal deficiency for distal 7 were markedly retarded with small placentae. No albino foetuses were found when the father was c/c and mother wild type, which suggested earlier lethality. Equivalent crosses with uw (chromosome 15) as proximal marker gave normal underwhite progeny when the mother was uw/uw but small placentae, retardation and neonatal death of presumptive underwhites in the reciprocal cross. These abnormal newborn would have had a maternal duplication/paternal deficiency for proximal 7. These and other findings indicate that one region of defective complementation probably lies distal to the breakpoint of T(7;18)50H at 7E2-F2, while another is between the centromere and 7B3. Examination of man-mouse homologies suggests that the loci for three pathological human conditions (Beckwith-Weidemann syndrome, dystrophia myotonia and rhabdomyosarcoma) with differential parental transmission may be located in homologous regions to those affected by imprinting phenomena on mouse chromosome 7.
Asunto(s)
Cromosomas , Cruzamientos Genéticos , Genes , Translocación Genética , Animales , Femenino , Prueba de Complementación Genética , Marcadores Genéticos , Masculino , RatonesRESUMEN
Albinism in laboratory mammals is equivalent to human tyrosinase-negative oculocutaneous albinism, and thus the result of recessive mutation in the structural locus for tyrosinase (TYR), which prevents melanin biosynthesis. In the mouse, eight mutant alleles are now known at this locus, with differing effects on eye colour and on the degree of reduction in eumelanin and phaeomelanin pigmentation. Three of these alleles, namely chinchilla, himalayan (acromelanistic) and albino (c) itself, have also been recognized in a number of other species but only albino has been identified in man so far. The himalayan allele (equivalent to Siamese in the cat) is of particular interest because it converts tyrosinase into a thermolabile form, with greater production of melanin in colder areas of the body. The optic track misrouting found in human albinos also occurs in albino alleles in other mammals, which may also show reduced activity and stress responses. The TYR locus is on human chromosome 11, which now has at least 11 loci with homologues on mouse 7. However, their order is markedly different in the two species. For instance, c and Hbb (beta-globin), which are closely linked in mouse, rabbit, cat etc., are far apart on human 11q and 11p respectively. Moreover, some loci (e.g., Fes and Mod-2) which are close to c in the mouse appear to be on human chromosomes other than 11. This extensive chromosomal restructuring in mammalian evolution means that the effects of human albino deletions may differ greatly from those studied in the mouse, which are associated with defects of kidney, liver and thymus. Tyrosinase-positive albinos or near-albinos are known at a number of loci in mice and other mammals. They are the result of the absence or inhibition of melanocytes in the affected areas, so that no melanin is produced. In general they are associated with pathological pleiotropisms which may lead to anaemia, inner ear defects, megacolon, neurological effects, skeletal defects, microphthalmia, osteopetrosis, spina bifida, sterility and so on. Homologies between these and human loci affecting pigmentation are now being discovered.
Asunto(s)
Albinismo/genética , Albinismo Ocular/genética , Albinismo Oculocutáneo/genética , Alelos , Animales , Deleción Cromosómica , Color del Ojo , Humanos , Melaninas/biosíntesis , Melanocitos/metabolismo , Monofenol Monooxigenasa/genética , Mutación/genéticaAsunto(s)
Mapeo Cromosómico , Animales , Ligamiento Genético , Humanos , Ratones , Homología de Secuencia de Ácido NucleicoRESUMEN
Current knowledge of man-mouse genetic homology is presented in the form of chromosomal displays, tables and a grid, which show locations of the 322 loci now assigned to chromosomes in both species, as well as 12 DNA segments not yet associated with gene loci. At least 50 conserved autosomal segments with two or more loci have been identified, twelve of which are over 20 cM long in the mouse, as well as five conserved segments on the X chromosome. All human and mouse chromosomes now have conserved regions; human 17 still shows the least evidence of rearrangement, with a single long conserved segment which apparently spans the centromere. The loci include 102 which are known to be associated with human hereditary disease; these are listed separately. Human parental effects which may well be the result of genomic imprinting are reviewed and the location of the factors concerned displayed in relation to mouse chromosomal regions which have been implicated in imprinting phenomena.
Asunto(s)
Mapeo Cromosómico , Cromosomas Humanos , Cromosomas , Ratones/genética , Animales , Evolución Biológica , ADN/genética , Reordenamiento Génico , Genes , Enfermedades Genéticas Congénitas/genética , Ligamiento Genético , Humanos , Homología de Secuencia de Ácido NucleicoRESUMEN
Intercrosses of mice doubly heterozygous for Rb(6.15)1A1d and Rb(4.15)4Rma (thus are characterized by monobrachial homology for chromosome 15) produced embryos with zero to four copies of chromosome 15 in their expected frequencies at the first cleavage division. By 3 1/2 days' gestation, nullisomy 15 embryos were missing. At 8 1/2 to 9 1/2 days, no monosomy 15 embryos were found, although trisomy 15 and tetrasomy 15 embryos were still present in their expected numbers. Tetrasomics were more severely affected than trisomics at this gestational age; the former were severely retarded "streak" embryos, while the latter had open neural tubes and were 2/3 the size of euploid embryos. The functional activity of chromosomes during the embryonic development of autosomal aneuploids is discussed in light of these findings.
Asunto(s)
Aberraciones Cromosómicas/embriología , Desarrollo Embrionario y Fetal , Ratones Mutantes/embriología , Animales , Aberraciones Cromosómicas/genética , Deleción Cromosómica , Trastornos de los Cromosomas , Embrión de Mamíferos/patología , Femenino , Muerte Fetal/genética , Masculino , Ratones , Ratones Mutantes/genética , Monosomía , No Disyunción Genética , Embarazo , Translocación Genética , TrisomíaRESUMEN
The effect of 2.0 Gy X-irradiation at different times during foetal and early post-natal development on the resultant somatic mutation frequency was investigated by scoring for changes in follicular melanocyte morphology (nucleofugal vs. nucleopetal) in mice heterozygous for the recessive coat colour mutations dilute (d) and leaden (ln). Two peaks were observed following X-irradiation on days 12.5 and 17.5 post coitus (p.c.). The biomodal character of the mutation frequency with time of X-irradiation may be related to changes in the dynamics of the melanocyte population with foetal age. Nonetheless, the results validate the treatment time used in the pilot study (Searle and Stephenson, 1982) as the most sensitive to the induction of somatic mutations within the follicular melanocyte population.
Asunto(s)
Melanocitos/efectos de la radiación , Mutación , Piel/efectos de la radiación , Envejecimiento , Animales , Desarrollo Embrionario y Fetal , Femenino , Edad Gestacional , Masculino , Melanocitos/citología , Ratones , Ratones Mutantes , Embarazo , Piel/embriología , Piel/crecimiento & desarrollo , Rayos XRESUMEN
Data on loci whose positions are known in both man and mouse are presented in the form of chromosomal displays, a table, and autosomal and X-chromosomal grids. At least 40 conserved autosomal segments with two or more loci, as well as 17 homologous X-linked loci, are now known in the two species, in which mitochondrial DNA is also highly conserved. Apart from the Y, the only chromosome now lacking a conserved group is human 13. Human 17 has a single conserved group which includes both short and long arms, and so may have remained largely intact in mammalian evolution. Human and mouse chromosomal maps show the approximate locations of homologous genes while the mouse map also shows the positions of translocations used in gene location.
Asunto(s)
Secuencia de Bases , Mapeo Cromosómico , Homología de Secuencia de Ácido Nucleico , Animales , Bandeo Cromosómico , Ligamiento Genético , Humanos , Cariotipificación , Ratones , Cromosoma XRESUMEN
In order to identify radiosensitive mutations in mice, 26 genetically well defined mutations in 26 different combinations of homozygous, hemizygous or heterozygous conditions, together with normal mice and mutagen-sensitive MS/Ae mice were analysed for the induction of micronuclei by X-rays in bone-marrow cells. For each mutant two doses of 0.5 and 1.0 Gy, two sampling times of 18 and 27 h after irradiation and unirradiated controls were studied. Using our criteria, homozygous contrasted allele of steel (Slcon), scabby (scb), viable dominant spotting (Wv), quaking (qk), fidget (fi) and postaxial hemimelia (px), heterozygous lurcher (Lc), hemizygous gyro (Gy), the compounds Slcon/grizzle-belly (SlgbH) and Wv/rump-white (Rw) and MS/Ae mice, were regarded as radiosensitive, with Slcon/Slcon the highest in rank order. Homozygous wabbler-lethal (wl) and wasted (wst) showed hyposensitivity which for the latter may be connected with enhanced cell killing.
Asunto(s)
Aberraciones Cromosómicas , Ratones Mutantes/genética , Efectos de la Radiación , Animales , Eritrocitos Anormales/ultraestructura , Femenino , Humanos , Masculino , Ratones , Cromosoma X , Rayos XRESUMEN
The mutant genes of the Syrian hamster, which were originally designated as brown (b) and rust (r), are shown by morphological and phenotypic criteria, as well as by linkage studies in the case of brown, to be homologous with pink-eyed dilution (p) and brown (b), respectively, two well established loci in the genetics of mammalian pigmentation. It is proposed that the two mutants be appropriately redesignated.
Asunto(s)
Cricetinae/genética , Color del Cabello , Mesocricetus/genética , Mutación , Animales , Cabello/citología , Ratones , Especificidad de la EspecieRESUMEN
Haematological information on steel (Sl) mice is limited largely to Sl/Sld mice of Bar Harbor stock (WC.B6 F1). Therefore, two Harwell alleles, SlgbH and Slcon, were investigated. In the steady state both heterozygotes were modestly anaemic, homozygous Slcon and compound Slcon/SlgbH more so. On perturbation by X-irradiation Slcon/SlgbH showed a decrease in median lethal dose (MLD)--6.5 Gy, Slcon/+ and Slcon/Slcon slightly less change (7.5 Gy) compared with +/+, 8 Gy. In recovery from sublethal doses single heterozygotes, double heterozygotes with Wv, and compounds showed no delay in restoration of the count of red blood corpuscles (RBC) such as that seen in typical W mice (e.g. Wv/+, W/Wv). Effects on Slcon/Slcon and Slcon/SlgbH differ from those reported for Sl/Sld in that they show normal growth of spleen colonies when used as lethally irradiated recipients of bone marrow, they support growth of implanted bone marrow to form radiation chimaeras. When Harwell steel mice are donors of bone marrow to lethally irradiated +/+ mice the chimaeras ultimately are not anaemic; when lethally irradiated Harwell steel mice are recipients of +/+ marrow they remain macrocytically anaemic. One deduces that, for normal development and production of normal RBC in the steady state, the erythron requires intrinsic factors determined by wild type alleles at the W locus and extrinsic factors determined by wild type alleles at the Sl locus. Mutant alleles at either locus may determine macrocytosis. Two mutant alleles at either locus are still more deleterious, often lethal. Whereas mutant W alleles may also influence the pluripotent haematopoietic stem cell (HSC) leading to reduced MLD on X-irradiation, a similarly reduced MLD for Sl mutants may represent an increased need for and consumption of products of the haematopoietic stem cells rather than truly increased radiosensitivity, since the Do for spleen colony-forming units is the same for Slcon/SlgbH as +/+ mice.
Asunto(s)
Hematopoyesis/efectos de la radiación , Animales , Recuento de Células Sanguíneas , Células Madre Hematopoyéticas/efectos de la radiación , Ratones , Ratones Mutantes , Quimera por Radiación , Dosis de Radiación , Tolerancia a RadiaciónRESUMEN
Hybrid male mice were exposed to 2.45 GHz microwaves for 30 min/day, 6 days a week for two consecutive weeks at power densities of 1.0, 100 or 400 W m-2, with sham-exposed controls. Rectal temperatures before and after exposure were measured on days 1, 6 and 12. Measurements made on day 1 were treated with caution because of heterogeneity in rectal temperatures taken before exposure between the groups of mice given different treatments. On days 6 and 12, rectal temperatures rose by approximately 1 degree C in mice sham exposed, or exposed to 1 W m-2 or 100 W m-2. Only in the group of mice exposed to 400 W m-2 was the mean rise in rectal temperature during exposure (about 3 degrees C) significantly increased above the sham value. In groups killed 2-3 days after treatment (mainly meiotic exposure) frequencies of chromosome aberrations in spermatocytes showed no significant heterogeneity although the highest frequency of 1.5 per cent was at the highest (400 W m-2) power density. Another group killed 30 days after 100 W m-2 exposures (spermatogonial sampling) showed no significant increase over controls in chromosome aberration frequency. There was a small but significant increase in sperm count with increasing power density in mice killed 12-13 days after exposure, but a non-significant one in those exposed as spermatogonia (killed 41 days later). Thus effects were markedly less severe than those reported previously by Manikowska-Czerska et al. (1985) with a very similar radiation regime and were probably caused by the temperature enhancement.
Asunto(s)
Aberraciones Cromosómicas , Microondas/efectos adversos , Espermatozoides/efectos de la radiación , Animales , Temperatura Corporal , Masculino , Ratones , Tamaño de los Órganos , Cromosomas Sexuales/efectos de la radiación , Recuento de Espermatozoides , Espermatozoides/ultraestructuraRESUMEN
Since recent assessments of genetic risks from radiation have concentrated on harmful dominant effects, a quantitative assessment of risks from recessives is needed. Presumably, harmful recessives can arise at all loci coding for essential proteins (perhaps 10 000), but mutation to dominant alleles is likely to be a property of relatively few loci. While many recessives doubtless remain to be discovered, those known at present tend to have earlier and more severe effects than dominants. Induced recessive mutations can cause harm by partnership with a defective allele already established in the population; partnership with another recessive mutation induced at the same locus; the formation of homozygous descendants, that is, identity by descent; and heterozygous effects. Calculations based on a combination of data from observations on human populations and from mouse experiments suggest that an extra genetically significant dose of 1 cGy (centiGray, equivalent to 1 rad) X or gamma irradiation received by each parent in a stable population with a million liveborn offspring would induce up to 1200 extra recessive mutations. From partnership effects, about one extra case of recessive disease would be expected in the following 10 generations. Homozygosity resulting from identity by descent could not normally occur until the fourth generation after exposure but, on certain assumptions, about ten extra cases of recessive disease would be expected from this cause by the tenth generation. In the same period, about 250 recessive alleles would be eliminated in heterozygotes (that is, Muller's 'genetic deaths') given 2.5% heterozygous disadvantage. These deleterious heterozygous effects should not be combined with those of dominants, as has been done in some previous risk estimates. It is considered unlikely that many radiation induced recessives would show heterozygous advantage. Certain dominants (combined frequently at least 10(-3)) should be excluded from calculations of mutational risk because they are unlikely to be maintained by mutation.
Asunto(s)
Genes Recesivos , Mutación , Genética de Radiación , Anomalías Inducidas por Radiación/genética , Alelos , Animales , Mapeo Cromosómico , Rayos gamma , Enfermedades Genéticas Congénitas/etiología , Heterocigoto , Homocigoto , Humanos , Ratones , Modelos Genéticos , Riesgo , Rayos XRESUMEN
The coat and eye colour mutant beige (bg) leads to the production of distinctive retinal melanocytes with abnormally large pigment granules. Heterozygotes for bg were given 2 Gy acute X-irradiation at various times between day 11.5 of fetal life and 3 days after birth, at which age whole mounts were prepared of the retinal pigmented epithelium (RPE). These were scanned for the presence of mutant retinal melanocytes with large granules, either as single cells or as clones. The earlier the fetal irradiation, the greater was the effect on RPE area at 3 days post-partum (p.p.), which fell to about half normal with the 11.5-day fetal exposures. However, the ultimate size of the retinal melanocytes seemed little affected by the irradiation, although their normal size increased approximately 3-fold between 12.5 days post-coitum (p.c.) and 3 days p.p. Mean numbers of mutant melanocytes per eye were markedly higher than in +/bg controls at all irradiation ages other than 3 days p.p.; when allowance was made for final sizes of irradiated RPE's mutation frequencies fell steadily from 30.0 x 10(-5) at 11.5 days p.c. to 1.0 x 10(-5) at 3 days p.p., with 0.8 x 10(-5) in +/bg and 0.1 x 10(-5) in +/+ controls. The doubling dose of 0.18 Gy at 16.5 days p.c. was similar to that found at 17.5 days p.c. in a previous somatic mutation experiment in which follicular melanocytes were scanned for mutations at different (d and ln) loci.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Melanocitos/efectos de la radiación , Mutación , Retina/efectos de la radiación , Envejecimiento , Animales , Femenino , Edad Gestacional , Masculino , Melanocitos/citología , Ratones , Índice Mitótico/efectos de la radiación , Retina/citología , Retina/embriología , Rayos XRESUMEN
Wasted (wst) is a spontaneous mutation with autosomal recessive inheritance. Abnormally low levels of adenosine deaminase have been found in erythrocytes from the wasted mouse. Enzyme activity in wst/wst mice is reduced to 38% of that found in the erythrocytes from control mice, and the apparent Km for adenosine is reduced to 51% of control. These changes imply an alteration in the catalytic properties of the enzyme arising from a change in the primary structure of the protein. We postulate that wasted is a mutation in the structural gene for adenosine deaminase. In man, the autosomal recessive form of severe combined immunodeficiency is associated, in about one-third of cases, with a deficiency of adenosine deaminase. Wasted mice are immunodeficient, develop neurological abnormalities, and die soon after weaning. These features are shared with the human syndrome. We therefore further suggest that the wasted mouse is an animal model for this form of severe combined immunodeficiency that will have potential use in gene-therapy studies.