RESUMO
Charcot-Marie-Tooth disease is an heterogeneous group of inherited peripheral motor and sensory neuropathies with several modes of inheritance: autosomal dominant, X-linked and autosomal recessive. By homozygosity mapping, we have identified, in the 5q23-q33 region, a third locus responsible for an autosomal recessive form of demyelinating CMT. Haplotype reconstruction and determination of the minimal region of homozygosity restricted the candidate region to a 4 cM interval. A physical map of the candidate region was established by screening YACs for microsatellites used for genetic analysis. Combined genetic, cytogenetic and physical mapping restricted the locus to a less than 2 Mb interval on chromosome 5q32. Seventeen consanguineous families with demyelinating ARCMT of various origins were screened for linkage to 5q31-q33. Three of these seventeen families are probably linked to this locus, indicating that the 5q locus accounts for about 20% of demyelinating ARCMT. Several candidate genes in the region were excluded by their position on the contig and/or by sequence analysis. The most obvious candidate gene, EGR1, expressed specifically in Schwann cells, mapped outside of the candidate region and no base changes were detected in two families by sequencing of the entire coding sequence.
Assuntos
Doença de Charcot-Marie-Tooth/genética , Cromossomos Humanos Par 5 , Proteínas de Ligação a DNA/genética , Proteínas Imediatamente Precoces/genética , Fatores de Transcrição/genética , Dedos de Zinco/genética , Sequência de Bases , Mapeamento Cromossômico , Proteína 1 de Resposta de Crescimento Precoce , Ligação Genética , Homozigoto , Humanos , Repetições de Microssatélites , Dados de Sequência Molecular , LinhagemRESUMO
X-linked dominant inheritance was suspected in a large family with Charcot-Marie-Tooth disease since no male to male transmission was observed, and since the sensory and motor neuropathy was more severe in males than in females. To test linkage to the dominant X-linked Charcot-Marie-Tooth disease (DCMTX) locus in Xq13, genotypes of 19 affected and 19 unaffected individuals from this family were determined for 4 microsatellite markers. Close linkage to mfd66 (DXS453) was found by bipoint analysis (Zmax = 4.8 at theta = 0.00). Multipoint analysis mapped the gene between the androgen receptor and DXYS1. In addition, linkage analysis performed with 11 microsatellite markers, derived from a high density map spanning 16 cM on Xq11-Xq21 revealed 3 new tightly linked loci: afm287zg1 (DXS1216), afm261zh5 and afm207zg5 (DXS995). Multipoint analysis localized the DCMTX gene to a 7.5 cM interval between afm123xd4 (DXS988) and afm116xg1 (DXS986). Combined analysis with these new microsatellites provides a powerful tool for carrier detection because of their high informativity and the small genetic distance (< 10 cM) between the markers flanking the gene.
Assuntos
Doença de Charcot-Marie-Tooth/genética , Genes Dominantes , Ligação Genética , Cromossomo X , Western Blotting , Mapeamento Cromossômico , DNA Satélite/genética , Feminino , Marcadores Genéticos/genética , Genótipo , Humanos , Masculino , Linhagem , Reação em Cadeia da Polimerase , Receptores Androgênicos/metabolismoRESUMO
BACKGROUND: Charcot-Marie-Tooth (CMT) disease is a heterogeneous group of inherited peripheral motor and sensory neuropathies with several modes of inheritance: autosomal dominant, X-linked, and autosomal recessive (AR) CMT. A locus responsible for the demyelinating form of ARCMT was assigned to the 5q23-q33 region (CMT4C) by homozygosity mapping. Recently, 11 mutations were identified in the SH3TC2 (KIAA1985) gene in 12 families with demyelinating ARCMT from Turkish, Iranian, Greek, Italian, or German origin. OBJECTIVE: To identify mutations in the SH3TC2 gene. METHODS: The authors searched for SH3TC2 gene mutations in 10 consanguineous CMT families putatively linked to the CMT4C locus on the basis of haplotype segregation and linkage analysis. RESULTS: Ten families had mutations, eight of which were new and one, R954X, recurrent. Six of the 10 mutations were in exon 11. Onset occurred between ages 2 and 10. Scoliosis or kyphoscoliosis and foot deformities were found in almost all patients and were often inaugural. The median motor nerve conduction velocity values (=34 m/s) were not correlated with disease duration. The functional disability score was =3, indicating that the patients could walk without help. Unexpectedly, typical giant axons were observed on biopsies from a large Algerian family. CONCLUSIONS: Charcot-Marie-Tooth type 4C (CMT4C) is less severe than other autosomal recessive (AR) CMT. Intrafamilial variability is important, making phenotype-genotype correlations difficult, but spine deformities are clearly a hallmark of CMT4C. In the presence of scoliosis, a neurologic examination is recommended. Giant axons on biopsies are also suggestive of CMT4C. For genetic analysis, the R954X mutation should be looked for before systematic sequencing of exon 11.
Assuntos
Doença de Charcot-Marie-Tooth/epidemiologia , Doença de Charcot-Marie-Tooth/genética , Medição de Risco/métodos , Curvaturas da Coluna Vertebral/epidemiologia , Curvaturas da Coluna Vertebral/genética , Coluna Vertebral/anormalidades , Mapeamento Cromossômico , Análise Mutacional de DNA , Feminino , França/epidemiologia , Predisposição Genética para Doença/epidemiologia , Predisposição Genética para Doença/genética , Humanos , Incidência , Masculino , Mutação , Linhagem , Fatores de RiscoRESUMO
Children with trisomy 21 are only a part of conceptuses with this anomaly which leads mainly to early arrests of development. Growth retardation of embryo and placenta are the main characteristics of these abortuses. Cell lines were established from tissues of trisomics 21 of different types of evolution (early spontaneous abortions, abortions after prenatal diagnosis, stillbirths and newborn-infants). Differences in the in vitro growth characteristics of these cells have been evidenced. They may explain the variations in the developmental potentials of trisomy 21 conceptuses.
Assuntos
Síndrome de Down/genética , Trissomia , Linhagem Celular , Aberrações Cromossômicas , Transtornos Cromossômicos , Feminino , Humanos , Técnicas In Vitro , Recém-Nascido , GravidezRESUMO
A linkage analysis between the Hunter syndrome locus (IDS) and four polymorphic loci of the Xq27-Xq28 region, DXS105, DXS98, DXS304, and DXS52, was performed in large families. A significant lod score was obtained between DXS304 and the Hunter gene (Zmax = 6.57 at theta max = 0.0). The Hunter gene can be localized within 7 cM of this marker. In addition, the translocation breakpoint of the Hunter female case described by J. Mossman et al. (1986, Arch. Dis. Child. 58: 911-915) was localized between DXS98 and DXS304 using somatic cell hybrids. These two results are in agreement and give the following order: DXS105-DXS98-IDS-DXS304-DXS52. Probes for these marker loci can thus be used for carrier detection.
Assuntos
Ligação Genética , Mucopolissacaridose II/genética , Cromossomo X , Animais , Mapeamento Cromossômico , Cricetinae , Feminino , Genes , Marcadores Genéticos , Humanos , Células Híbridas , Escore Lod , Masculino , Camundongos , LinhagemRESUMO
HLA associations with 21-OH deficiency were studied on respectively 109 and 60 congenital and late onset French index cases. Significant negative associations were found with antigens B8: congenital forms; B5, DR3: late onset. Significant positive associations were observed with A3, Bw47 (A3 Cw6 Bw47 DR7): congenital forms; B40: salt-wasting form; B5: simple virilizing form; Aw33, B14, DR1, DR2, DRw6 (Aw33 B14 DR1): late onset form. Among late onset patients not bearing B14 antigens significant positive associations were observed with B12 and B35.
Assuntos
Hiperplasia Suprarrenal Congênita , Antígenos HLA/genética , Complexo Principal de Histocompatibilidade , Esteroide Hidroxilases/deficiência , Hiperplasia Suprarrenal Congênita/genética , Alelos , Diagnóstico Diferencial , França , Heterozigoto , Homozigoto , Humanos , Mutação , Linhagem , PuberdadeRESUMO
Hereditary motor and sensory neuropathy type I (HMSN I), also designated Charcot-Marie-Tooth disease type 1 (CMT1), is a peripheral neuropathy frequently inherited as an autosomal dominant trait, characterised by progressive distal muscular atrophy and sensory loss with markedly decreased nerve conduction velocity. A duplication within chromosome 17p11.2, cosegregating with the disease, has recently been reported in several CMT1a families. In order to estimate the frequency of this anomaly and determine the location of a duplication in this region, 12 CMT1 families were analysed with polymorphic DNA markers located within 17p11.2-12. Duplications were found in all families including loci D17S61 (EW401), D17S122 (VAW409R3a and RM11-GT), and D17S125 (VAW412R3). The duplications were completely linked and associated with the disease (lod score of 20.77 at zero recombination). Screening for the RM11-GT microsatellite showed that most of the duplicated haplotypes were heterozygous, supporting the hypothesis that the duplication resulted from an unequal crossing over. There was no significant haplotype association within the duplicated region suggesting that the duplication resulted de novo as an independent event in each family. In one family, recombination within the duplicated region was observed, indicating that genetic instability in 17p11.2 might be related to a high recombination rate. Since most cases of CMT1a seem to result from this segmental trisomy, it can be used as a basis for DNA diagnosis of the disease.
Assuntos
Doença de Charcot-Marie-Tooth/genética , Cromossomos Humanos Par 17 , Família Multigênica , Sequência de Bases , Doença de Charcot-Marie-Tooth/diagnóstico , Doença de Charcot-Marie-Tooth/fisiopatologia , DNA/genética , Sondas de DNA , DNA Satélite/genética , Feminino , França , Ligação Genética , Humanos , Masculino , Dados de Sequência Molecular , Condução Nervosa , LinhagemRESUMO
Banding technique were applied to cell lines which had been established earlier from spontaneous human abortions and preserved frozen. Most of the autosomes were shown to be involved in lethal trisomies. As a result of the precise identification of affected chromosomes, the exact time of developmental arrest as well as certain phenotypes could be correlated with the various trisomies.
Assuntos
Aborto Espontâneo/genética , Aberrações Cromossômicas , Adulto , Citogenética , Feminino , Humanos , Ploidias , Gravidez , TrissomiaRESUMO
Twenty-eight HLA-A and B markers have been tested in 49 couples who had one or more triploid abortions. The antigen frequencies were compared to those of 209 couples and 591 normal individuals as controls. No significant deviations were observed. However, a non significant excess of antigens shared in common by both parents was shown in comparison with the normal couples. This could be related to a possible dispermy mechanism. On the other hand, a slight excess of A 28 may be in relation to a possible anomaly of gametogenesis.
Assuntos
Aborto Espontâneo/genética , Antígenos HLA/genética , Feminino , Antígenos HLA/análise , Humanos , Masculino , Fenótipo , Poliploidia , GravidezRESUMO
A pregnancy from a family at risk for fucosidosis was monitored. Determinations of fucosidase and mannosidase were performed on the serum and white blood cells of several members of the family, om amniotic fluid and amniotic fluid cells of the fetus at several passages, and on fibroblast cell lines from index cases. The fetus was diagnosed as being free from the disease. This conclusion was confirmed after birth by fucosidase determination in plasma and white cells from cord blood, and in the placenta. Fluctuations in fucosidase activity were observed in extracts from cultured amniotic cells at various passages. The possible causes of this variability are discussed.
Assuntos
Erros Inatos do Metabolismo dos Carboidratos/diagnóstico , Dissacaridases/deficiência , Diagnóstico Pré-Natal/métodos , alfa-L-Fucosidase/deficiência , Adulto , Líquido Amniótico/citologia , Líquido Amniótico/enzimologia , Erros Inatos do Metabolismo dos Carboidratos/genética , Células Cultivadas , Pré-Escolar , Feminino , Sangue Fetal/enzimologia , Feto/enzimologia , Fibroblastos/enzimologia , Humanos , Recém-Nascido , Leucócitos/enzimologia , Masculino , Manosidases/metabolismo , Gravidez , alfa-L-Fucosidase/metabolismoRESUMO
A family (father and daughter) was found with a deficiency of hexosaminidase (HEX A and HEX B). Residual HEX A activity was about 30% of usual heterozygotes with very little HEX B activity. Thermostability of HEX A was decreased. No immunological cross reacting material was found for HEX A or B. The mechanism seems to be the production of abnormal, unstable beta subunits, which are still capable of combining with alpha subunits to form functional HEX A.
Assuntos
Acetilglucosaminidase/metabolismo , Variação Genética , Hexosaminidases/metabolismo , Adulto , Feminino , Fibroblastos/enzimologia , Heterozigoto , Humanos , Imunoeletroforese , Lactente , Leucócitos/enzimologia , Lipidoses/diagnóstico , MasculinoRESUMO
Indirect hemagglutination test for detection of antibodies to cytomegalovirus is highly sensitive and reproducible, if employed in well-defined conditions. Standardization of the various factors involved is necessary as well as their reciprocal equilibrium : sheep erythrocytes, antigen, dilution of tanin, buffers quality. The hemagglutination test can be performed on small volumes such as blood collection on blotting paper (PKU). Antibody titers were compared in the serum and the blood so collected in 104 subjects : the results were very similar and no "false negative" were found in any case. This way of collecting blood and hemagglutination are technical improvements in epidemiologic studies of cytomegalovirus infection. It can be hoped they will be adapted to other group herpes infections.
Assuntos
Anticorpos Antivirais/análise , Citomegalovirus/imunologia , Testes de Hemaglutinação/métodos , Animais , Coleta de Amostras Sanguíneas/métodos , Soluções Tampão , Infecções por Citomegalovirus/diagnóstico , Humanos , Ovinos/imunologia , TaninosRESUMO
The polymorphism of HLA antigens was used as a marker to investigate the genetic origin of hydatidiform moles in Senegal. An androgenetic etiology was demonstrated. When both parents shared HLA antigens a preferential inheritance in the mole of the shared specificities was observed. This relative compatibility of the molar conceptus with the mother may be an element of the process that prevents its early rejection.
Assuntos
Marcadores Genéticos , Antígenos HLA/genética , Mola Hidatiforme/genética , Neoplasias Uterinas/genética , Feminino , Humanos , Mola Hidatiforme/epidemiologia , Masculino , Polimorfismo Genético , Gravidez , Senegal , Neoplasias Uterinas/epidemiologiaRESUMO
Gene dosage studies yielded results consistent with the assignment of the locus for pyruvate kinase (PK3) to chromosome 15. The activity of seven cytoplasmic enzymes has been determined in fibroblast extracts from six trisomy 15 lines and 16 normal control lines. The fibroblast extracts from the trisomic patients had pyruvate kinase activity 57% higher than fibroblast extracts from control lines, while other enzyme activities were within the normal range of activity.
Assuntos
Alelos , Cromossomos Humanos 13-15 , Marcadores Genéticos , Isoenzimas/genética , Piruvato Quinase/genética , Trissomia , Linhagem Celular , Mapeamento Cromossômico , Embrião de Mamíferos , Glucose-6-Fosfato Isomerase/genética , Glucosefosfato Desidrogenase/genética , Humanos , Técnicas In Vitro , L-Lactato Desidrogenase/genética , Fosfogluconato Desidrogenase/genética , Fosfoglicerato Quinase/genética , Triose-Fosfato Isomerase/genéticaRESUMO
Seventy-one human x mouse hybrid cell lines were used to map the locus of a human alpha-3-fucosyltransferase to 11q. The enzyme transfers fucose onto H type 2 more efficiently than onto sialyl-N-acetyllactosamine, suggesting that it is the myeloid type of alpha-3-fucosyltransferase (Mollicone et al., 1990), which makes the 3-fucosyllactosamine epitope on polymorphonuclear cells and monocytes. This epitope is also known as CD15 (Tetteroo et al., 1987).
Assuntos
Cromossomos Humanos Par 11 , Fucosiltransferases/genética , Animais , Antígenos de Diferenciação/biossíntese , Southern Blotting , Sequência de Carboidratos , Mapeamento Cromossômico , Humanos , Células Híbridas , Antígenos CD15 , Camundongos , Dados de Sequência Molecular , Hibridização de Ácido NucleicoRESUMO
X; autosomal translocations are excellent tools for genetic analysis because of the easy selection of clones isolating the derivative bearing the HPRT gene in somatic cell hybrids. We have developed a strategy to select clones isolating the other derivative avoiding fastidious and time consuming technics, mainly based on immunofluorescent screening using MIC 2 and MIC 5 antigenic markers and we have succeeded in isolating in a rodent context the two X;5 translocated derivative chromosomes of a female patient with Hunter syndrome. The location of MIC 5 gene was specified between the IDS and G6PD DXS369 (RN1), DXS296 (VK21c), and DXS304 (U62), DXS52 and F8c (F814) are proximal and distal from the breakpoint disrupting the IDS gene respectively.
Assuntos
Células Híbridas/ultraestrutura , Mucopolissacaridose II/genética , Translocação Genética/genética , Cromossomo X , Anticorpos Monoclonais , Southern Blotting , Fusão Celular , Linhagem Celular , Células Clonais , Feminino , Imunofluorescência , HumanosRESUMO
The results of early prenatal diagnoses of congenital adrenal hyperplasia are reported. The determination of 17-hydroxyprogesterone values in amniotic fluid taken transabdominally at 11 weeks of gestation enabled prenatal diagnosis of congenital adrenal hyperplasia due to 21-hydroxylase (21-OH) deficiency. There is a clear-cut difference between normal and pathological values at that time of pregnancy. This method of diagnosis can be combined with genotyping of the fetus by HLA-DNA probes on chorionic villus sampling or can be used alone. Prenatal diagnosis with a 21-OH probe is possible when a preliminary study has demonstrated that the index case is homozygous for the deletion.
Assuntos
Hiperplasia Suprarrenal Congênita , Hiperplasia Suprarrenal Congênita/diagnóstico , Amniocentese , Líquido Amniótico/análise , Amostra da Vilosidade Coriônica , Sondas de DNA de HLA , Sondas de DNA , Hidroxiprogesteronas/análise , Esteroide Hidroxilases/deficiência , 17-alfa-Hidroxiprogesterona , Hiperplasia Suprarrenal Congênita/genética , Feminino , Humanos , GravidezRESUMO
Charcot-Marie-Tooth (CMT) disease is the most frequent inherited peripheral motor and sensory neuropathy characterised by chronic distal weakness with progressive muscular atrophy and sensory loss of the distal extremities. The dominant form of the disease is genetically heterogeneous but only one locus has been identified on chromosome 8q13-q21.1 for autosomal recessive CMT. By homozygosity mapping in a large Algerian kindred, we have assigned a second locus for autosomal recessive CMT to chromosome 5q23-33. Linkage analysis demonstrated that the same locus is involved in a second Algerian family with a demyelinating CMT. Haplotype reconstruction and determination of the minimal region of homozygosity restricts the candidate region to a 4 cM interval.