RESUMO
Usher syndrome type 1C (USH1C) occurs in a small population of Acadian descendants from southwestern Louisiana. Linkage and linkage disequilibrium analyses localize USH1C to chromosome 11p between markers D11S1397 and D11S1888, an interval of less than 680 kb. Here, we refine the USH1C linkage to a region less than 400 kb, between genetic markers D11S1397 and D11S1890. Using 17 genetic markers from this interval, we have isolated a contiguous set of 60 bacterial artificial chromosomes (BACs) that span the USH1C critical region. Exon trapping of BAC clones from this region resulted in the recovery of an exon of the nuclear EF-hand acidic (NEFA) gene. However, DNA sequence analysis of the NEFA cDNA from lymphocytes of affected individuals provided no evidence of mutation, making structural mutations in the NEFA protein unlikely as the cellular cause of Acadian Usher syndrome.
Assuntos
Mapeamento Cromossômico , Cromossomos Humanos Par 11 , Proteínas de Ligação a DNA/genética , Perda Auditiva Neurossensorial/genética , Retinose Pigmentar/genética , Bacteriófago P1/genética , Proteínas de Ligação ao Cálcio , Canadá/etnologia , Cromossomos Artificiais de Levedura , Clonagem Molecular , França/etnologia , Perda Auditiva Neurossensorial/classificação , Perda Auditiva Neurossensorial/epidemiologia , Humanos , Louisiana/epidemiologia , Repetições de Microssatélites , Proteínas do Tecido Nervoso , Nucleobindinas , Retinose Pigmentar/classificação , Retinose Pigmentar/epidemiologia , Análise de Sequência de DNA , SíndromeRESUMO
PURPOSE: To refine the map position of the Usher syndrome type 1C (USH1C) locus to 11p14-p15.1 in the French-Acadian population settled in Louisiana. METHODS: Linkage and haplotype analysis of Ush1C in the French-Acadian families from southwestern Louisiana was carried out using additional markers known to map to the USH1C interval. Markers localized to 11p were also mapped on the J1 somatic cell hybrid panel. This analysis also helped to localize precisely the USH1C interval. RESULTS: New flanking markers for USH1C have been identified, localizing the USH1C gene to a 1 cM interval between markers D11S1397 and D11S1888. Markers D11S1890 and D11S1888 were placed within the USH1C interval. Analysis of all the markers in the USH1C region flanked by D11S1397 and D11S1888 on the J1 somatic cell hybrid panel localized USH1C to the upper half of chromosome 11p14. CONCLUSION: The Usher Syndrome type 1C gene has been localized to a 1 cM interval between the markers D11S1397 and D11S1888 on chromosome 11p14.
Assuntos
Cromossomos Humanos Par 11 , Perda Auditiva Neurossensorial/genética , Retinose Pigmentar/genética , Canadá/etnologia , Mapeamento Cromossômico , França/etnologia , Haplótipos , Humanos , Louisiana , Repetições de Microssatélites/genética , SíndromeRESUMO
During the past half century reproductive and prenatal technologies have become increasingly sophisticated and accessible to the public. As prospective parents have become more knowledgeable about the various reproductive options available, there has evolved a body of jurisprudence that has defined and defended the exclusive right of individuals to make their own decisions about conceiving and bearing children. This right is now protected under the constitutional umbrella of the right to privacy. If this right is violated through the negligence of one or more health care providers, the allegedly injured parents may sue for the wrongful birth of an unplanned or a defective child. Similarly, a defective child may sue for wrongful life. Both plaintiff parents and plaintiff child seek to recover monetary damages as compensation for their alleged injuries. In wrongful birth cases judicial opinions have moved from an earlier "blessings rationale" through a series of "benefits" cases toward more recent "burdens" decisions. In early suits for wrongful life the courts often held that the child had no valid cause of action and could therefore not be heard in court. More recently, however, some courts have recognized the validity of actions for wrongful life and have decided in favor of the defective children. The most recent judicial decisions suggest that courts may be following a trend to decide in favor of plaintiff parents and children at the expense of the defendant health care providers.
Assuntos
Coeficiente de Natalidade , Imperícia/legislação & jurisprudência , Anormalidades Congênitas , Feminino , Aconselhamento Genético , Genética Médica , Humanos , Recém-Nascido , Gravidez , Estados UnidosRESUMO
As technical knowledge and public information in medical genetics continue to expand, the geneticist may expect to be held responsible for informing patients and clients about new developments in research and diagnosis. The long legal evolution of the physician's duty to disclose, and more recent findings of a physician's duty to recall former patients to inform them about newly discovered risks of treatment, indicate that medical geneticists may have a duty to disclose both current and future information about conditions that are or could be inherited. Recent case law supports findings of professional liability for both present and future disclosure, even in the absence of an active physician-patient relationship. The requirement of candid and complete disclosure will affect the counseling approach in testing for deleterious genes and in providing medical treatment for minors with hereditary diseases. Finding a duty to recall may impose further professional burdens on the geneticist to reach beyond the immediate counseling arena and to recontact patients, perhaps years after their initial visit to genetics clinic.
Assuntos
Revelação , Genética Médica/legislação & jurisprudência , Revelação da Verdade , Beneficência , Criança , Aconselhamento Genético/legislação & jurisprudência , Doenças Genéticas Inatas/terapia , História do Século XX , Humanos , Consentimento Livre e Esclarecido/história , Consentimento Livre e Esclarecido/legislação & jurisprudência , Responsabilidade Legal , Imperícia , Menores de Idade , Princípios Morais , Consentimento dos Pais , Autonomia Pessoal , Relações Médico-Paciente , Medição de RiscoRESUMO
We report a patient with craniosynostosis, radial aplasia, imperforate anus, and several associated congenital anomalies. It is concluded that she has the Baller-Gerold syndrome. Parenteral consanguinity supports the suggestion that this condition is inherited in an autosomal recessive manner.
Assuntos
Anormalidades Múltiplas/genética , Canal Anal/anormalidades , Craniossinostoses/genética , Rádio (Anatomia)/anormalidades , Adolescente , Aberrações Cromossômicas , Transtornos Cromossômicos , Feminino , Humanos , Linhagem , SíndromeRESUMO
We describe a large consanguineous German-Acadian ("Cajun") family from a rural area in Louisiana in which 11 persons in two generations had the Maroteaux-Lamy syndrome. The mutant arylsulfatase B enzyme in this family was similar to the mutant enzyme in previously studied families in its cross-reactivity with specific antibodies to the enzyme, but it differed in both its electrophoretic mobility and its residual enzymatic activity. These findings indicate that a different mutational event leading to Maroteaux-Lamy syndrome occurred in this family.
Assuntos
Mucopolissacaridoses/genética , Mucopolissacaridose VI/genética , Criança , Condro-4-Sulfatase/genética , Condro-4-Sulfatase/imunologia , Condro-4-Sulfatase/isolamento & purificação , Consanguinidade , Feminino , Genes Recessivos , Humanos , Imunoquímica , Masculino , Mucopolissacaridose VI/enzimologia , Mucopolissacaridose VI/imunologia , MutaçãoRESUMO
We report on a patient with craniosynostosis, left radius aplasia, right radius hypoplasia, and other congenital anomalies. This is the 11th reported case of the Baller-Gerold syndrome. Autosomal recessive inheritance of this syndrome is suggested by evidence of probable parental consanguinity.
Assuntos
Anormalidades Múltiplas , Craniossinostoses , Rádio (Anatomia)/anormalidades , Criança , Consanguinidade , Feminino , Genes Recessivos , Transtornos do Crescimento , Humanos , Deficiência Intelectual , Convulsões , Crânio/anormalidades , SíndromeRESUMO
A number of Usher syndrome (USH) families are found among the French-Acadians living in southwestern Louisiana. These families are descended from a few common ancestors, suggesting that USH may be homogeneous within this ethnic group. However, we report distinct phenotypic variability. Based on differences in psychomotor development and tests of auditory and vestibular function, Acadian individuals with both USH Type 1 and Type 2 can be identified. One additional family, with unusual findings, represents a third clinical phenotype. Linkage data strongly support these clinical observations.
Assuntos
Cegueira/genética , Transtornos da Audição/genética , Cromossomos Humanos Par 1 , Etnicidade , Feminino , Marcadores Genéticos , Transtornos da Audição/classificação , Humanos , Louisiana , Masculino , Linhagem , Fenótipo , SíndromeRESUMO
The Usher syndromes are genetically distinct disorders which share specific phenotypic characteristics. This paper describes a set of clinical criteria recommended for the diagnosis of Usher syndrome type I and Usher syndrome type II. These criteria have been adopted by the Usher Syndrome Consortium and are used in studies reported by members of this Consortium.
Assuntos
Perda Auditiva Neurossensorial/congênito , Perda Auditiva Neurossensorial/diagnóstico , Retinose Pigmentar/diagnóstico , Doenças Vestibulares/diagnóstico , Diagnóstico Diferencial , Eletrorretinografia , Perda Auditiva Neurossensorial/genética , Humanos , Oftalmoscopia , Retinose Pigmentar/genética , Inquéritos e Questionários , Síndrome , Doenças Vestibulares/genética , Testes de Função VestibularRESUMO
Recent events in genetics research have generated questions about the efficacy of federal regulations that govern the conduct of biomedical research, particularly genetics research. The regulatory definitions of "human subject" and "private information" that have governed the conduct of research for two decades are presently under scrutiny because of ambiguities created by the methods of family studies in human and medical genetics. Geneticists customarily collect family history information for the purposes of tracking and characterizing genes in large families. Amassing family history information usually entails asking human subjects about the health status of collateral relatives. Whether these relatives should be regarded as human subjects for the purposes of giving informed consent is the issue that has triggered wide debate and an exhaustive re-examination of federal regulations and guidelines. The purpose of this article is threefold. First, a review of the development of current federal regulations provides a foundation and a point of departure for resolving current issues in genetics research. Second, a review of customary practices in genetics research furthers thought regarding regulations or guidelines to address specific issues in genetics. Third, it asserts that any new regulations or guidelines must provide appropriate protections for human subjects and their families while simultaneously supporting appropriate activities in genetics research.
Assuntos
Fiscalização e Controle de Instalações/legislação & jurisprudência , Privacidade Genética/legislação & jurisprudência , Linhagem , Pesquisa/normas , Bioética , Guias como Assunto , Experimentação Humana/legislação & jurisprudência , Humanos , Consentimento Livre e Esclarecido , Anamnese , Pesquisa/legislação & jurisprudência , Estados UnidosAssuntos
Interfase/genética , Diagnóstico Pré-Natal/métodos , Feminino , Humanos , Hibridização In Situ , GravidezRESUMO
Twelve persons in four generations of a rural family of mixed racial ancestry exhibited ankylosed teeth, bilateral clinodactyly of the fifth fingers, and abnormalities of the jaws. This previously undescribed association of dental, digital, and skeletal anomalies appears to be transmitted in an autosomal dominant manner in this family. Clinical manifestations in the examined persons and an extended family history are described in detail. Previous studies of apparently hereditary dental ankylosis are similarly discussed.
Assuntos
Dedos/anormalidades , Genes Dominantes , Anormalidades Maxilomandibulares/genética , Anormalidades Dentárias/genética , Adulto , Feminino , Humanos , Masculino , Linhagem , SíndromeRESUMO
Congenital universal muscular hypoplasia has been confused with similar diseases in the past. Evidence presented in this paper distinguishes this disorder from other phenotypically similar ones and indicates that it is inherited as an autosomal recessive disorder.
Assuntos
Genes Recessivos , Doenças Musculares/genética , Adulto , Biópsia , Consanguinidade , Feminino , Humanos , Masculino , Hipotonia Muscular/genética , Músculos/patologia , Linhagem , FenótipoRESUMO
Docosahexaenoate and arachidonate were found to be significantly decreased in plasma phospholipids from Usher's syndrome patients. The fatty acid content of plasma triacylglycerols was not changed in these patients. Usher's syndrome, an autosomal recessive disorder, involves an inherited visual cell degeneration. Photoreceptor membranes are richly endowed with docosahexaenoate and arachidonate, and a metabolic defect affecting these polyunsaturated fatty acids may occur. Moreover, blindness may be due, at least partially, to an alteration in the unsaturated phospholipids of photoreceptor membranes.
Assuntos
Ácidos Graxos Insaturados/sangue , Fosfolipídeos/sangue , Retinose Pigmentar/sangue , Ácido Araquidônico , Ácidos Araquidônicos/sangue , Ácidos Docosa-Hexaenoicos , Humanos , Células Fotorreceptoras/metabolismo , Síndrome , Triglicerídeos/sangueRESUMO
DNA linkage studies of human genetic diseases have led to rapid characterization of a number of otherwise intractable disease loci. Detection of a linked DNA marker, the first step in "reverse genetics", has permitted cloning of the genes for Duchenne muscular dystrophy, retinoblastoma and chronic granulomatosis disease, among others. Thus, the case for applying these techniques to retinitis pigmentosa and related diseases, and the urgency in capitalizing on molecular developments, is justified and compelling. The first major success regarding RP was in demonstrating linkage of the DNA marker DXS7 (L1.28) to XRP. For autosomal forms of the disease, conventional linkage studies have provided tentative evidence for linkage of ADRP to the Rh blood group on chromosome lp and for linkage of Usher's syndrome to Gc and 4q. These provisional assignments are, at least, an important starting point for DNA analysis. The Support Program for DNA Linkage Studies of Degenerative Retinal Diseases was established to provide access for the scientific community to appropriate families, using the resources of the Human Genetic Mutant Cell Repository to prepare, store and distribute lymphoblast lines. To date, two extensive, well-characterized families are included in the program: the autosomal dominant RP family UCLA-RP01, and the Usher's syndrome families LSU-US01. It is highly likely that rapid progress will be made in mapping and characterizing the inherited retinal dystrophies. We believe the support program will facilitate this progress.
Assuntos
DNA/genética , Ligação Genética , Degeneração Retiniana/genética , Corioide , Objetivos , Humanos , Apoio à Pesquisa como Assunto , Doenças Retinianas/genética , Retinose Pigmentar/genética , Doenças da Úvea/genéticaRESUMO
Usher syndrome type I is an autosomal recessive disease characterized by profound congenital hearing impairment and vestibular dysfunction followed by the onset of progressive pigmentary retinopathy in childhood or early adolescence. A locus (USH1C) for one form of this disease was previously assigned to the short arm of chromosome 11 through linkage studies in the Acadian population of southwestern Louisiana. Linkage analyses of a set of microsatellite markers in 27 Acadian families provide evidence that USH1C lies between D11S861 and D11S928. Three markers (D11S419, D11S921, and D11S899) that lie between the flanking markers show no recombination with USH1C, and all 54 chromosomes with the abnormal allele at the disease locus have identical alleles for D11S419 and D11S921. This haplotype was found on only 10 of 50 chromosomes with the normal allele at the disease locus, suggesting a strong founder effect. Of the 54 chromosomes with the abnormal allele, 12 had a divergent allele at D11S899. These results suggest that USH1C is in the 2-3-cM interval between D11S861 and D11S899.
Assuntos
Cromossomos Humanos Par 11 , Surdez/genética , Genética Populacional , Retinose Pigmentar/genética , DNA Satélite/análise , Surdez/congênito , Ligação Genética , Marcadores Genéticos , Haplótipos , Humanos , Escore Lod , Louisiana , Linhagem , Quebeque/etnologia , SíndromeRESUMO
Human leukocyte antigens (HLA) were identified in 22 black Americans with multiple myeloma. No significant association was observed between antigens at either the A or the B locus. At the C locus, in contrast, HLA-Cw5 was more prevalent in the patient group, four of 22 having it, compared with the control group, in which two of 138 individuals possessed it. All four patients with HLA-Cw5 were males. Those results suggest that genetic factors, perhaps in conjunction with an environmental change, may be responsible for the recent increase in incidence in myeloma in black Americans, especially in males.
Assuntos
Antígenos HLA/análise , Antígenos HLA-C , Mieloma Múltiplo/genética , Adulto , Idoso , População Negra , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores Sexuais , Estados UnidosRESUMO
Usher syndrome is an autosomal recessive disease characterized by dual sensory impairments; affected individuals are born with a sensorineural hearing loss and ultimately lose their sight as retinitis pigmentosa develops. Conventional protein markers previously tested in a Louisiana Acadian kindred suggested tentative linkage to vitamin D-binding protein on chromosome 4. DNA linkage studies do not confirm this linkage relationship and exclude much of chromosome 4 as the site of the Usher syndrome gene in these families.