RESUMO
Inherited retinopathies are a genetically and phenotypically heterogeneous group of diseases affecting approximately one in 2000 individuals worldwide. For the past 10 years, the Laboratory for Molecular Diagnosis of Inherited Eye Diseases (LMDIED) at the University of Texas-Houston Health Science Center has screened subjects ascertained in the United States and Canada for mutations in genes causing dominant and recessive autosomal retinopathies. A combination of single strand conformational analysis (SSCA) and direct sequencing of five genes (rhodopsin, peripherin/RDS, RP1, CRX, and AIPL1) identified the disease-causing mutation in approximately one-third of subjects with autosomal dominant retinitis pigmentosa (adRP) or with autosomal dominant cone-rod dystrophy (adCORD). In addition, the causative mutation was identified in 15% of subjects with Leber congenital amaurosis (LCA). Overall, we report identification of the causative mutation in 105 of 506 (21%) of unrelated subjects (probands) tested; we report five previously unreported mutations in rhodopsin, two in peripherin/RDS, and one previously unreported mutation in the cone-rod homeobox gene, CRX. Based on this large survey, the prevalence of disease-causing mutations in each of these genes within specific disease categories is estimated. These data are useful in estimating the frequency of specific mutations and in selecting individuals and families for mutation-specific studies.
Assuntos
Glicoproteínas de Membrana , Mutação , Retinose Pigmentar/epidemiologia , Retinose Pigmentar/genética , Substituição de Aminoácidos/genética , Animais , Arginina/genética , Cisteína/genética , Variação Genética , Glutamina/genética , Proteínas de Homeodomínio/genética , Humanos , Proteínas de Filamentos Intermediários/genética , Leucina/genética , Proteínas do Tecido Nervoso/genética , Atrofias Ópticas Hereditárias/genética , Periferinas , Prevalência , Prolina/genética , Degeneração Retiniana/genética , Doenças Retinianas/epidemiologia , Doenças Retinianas/genética , Rodopsina/genética , Transativadores/genética , Tirosina/genéticaRESUMO
Group specific component (Gc) is an abundant plasma protein whose functional role is not clearly established. Gc protein is synthesised in the liver and is known to bind vitamin D, vitamin D metabolites, and G actin; Gc protein is also implicated in macrophage activation. Several polymorphic electrophoretic variants of Gc protein are found in all human populations; the most common alleles are Gc-1f, Gc-1s, and Gc-2. In previous studies, Gc allele frequencies, determined using isoelectric focusing or immunofixation or both, were significantly different in patients with tuberous sclerosis complex (TSC) from matched controls, with an excess of Gc-2 in patients. Linkage association between Gc and TSC is unlikely since the Gc locus maps to chromosome 4q12, whereas the two common forms of TSC map to 9q34 and 16p13.1, respectively. However, a direct cause and effect relationship between Gc protein and TSC symptoms is possible. To investigate further the relationship between the Gc locus and TSC, two Gc restriction site polymorphisms, HaeIII and StyI, were typed in 43 unrelated white subjects with TSC. The frequencies of the restriction site polymorphisms in the TSC patients did not differ from those in control populations. Therefore a direct association between Gc type and TSC is unlikely. The previously reported association was either spurious or the result of typing errors in plasma from subjects with underlying abnormalities in plasma proteins.
Assuntos
Esclerose Tuberosa/genética , Proteína de Ligação a Vitamina D/genética , Sequência de Bases , Estudos de Coortes , Primers do DNA/genética , Frequência do Gene , Humanos , Fenótipo , Reação em Cadeia da Polimerase , Polimorfismo de Fragmento de Restrição , Esclerose Tuberosa/sangueRESUMO
Patients with pseudoachondroplasia have a skeletal dysplasia with marked short stature. The most common cause of this condition is an autosomal dominant mutation, although autosomal recessive inheritance has been reported. Linkage to 2 cartilage-specific candidate genes, type II collagen (COL2A1) and proteoglycan link protein genes (CRTL1), was tested in 9 autosomal dominant families with pseudoachondroplasia. Tight linkage to these candidate genes was excluded with LOD scores for COL2A1 of -2.45 at theta = 0.05 and for CRTL1 of -7.28 at theta = 0.001. Discordant inheritance of the disease phenotype with each of these genes was also observed. Thus, these 2 candidate genes can be excluded as the cause of disease in these families.
Assuntos
Colágeno/genética , Nanismo/genética , Proteoglicanas/genética , Feminino , Genes Dominantes , Ligação Genética , Humanos , Masculino , LinhagemRESUMO
Linkage of tuberous sclerosis complex (TSC), an autosomal dominant disorder, to markers on chromosome 9 was reported first in 1987. This assignment was confirmed by an international collaborative study that suggested more than one locus may be responsible for the phenotype. We studied 14 multigenerational TSC families (13 previously unreported) with markers for nine loci in the linked region of chromosome 9q32-q34. Our results confirm the previous reports that the genetic locus in one-third to one-half of families maps to chromosome 9. Comparison of clinical findings in the chromosome 9-linked families with those in the chromosome 9-unlinked families reveals only a higher incidence of ungual fibromata in the chromosome 9-linked families.
Assuntos
Cromossomos Humanos Par 9 , Polimorfismo Genético , Esclerose Tuberosa/genética , Alelos , Linhagem Celular , Mapeamento Cromossômico , Feminino , Fibroma/genética , Fibroma/patologia , Genes Dominantes , Ligação Genética , Marcadores Genéticos , Humanos , Masculino , Linhagem , Fenótipo , Probabilidade , Esclerose Tuberosa/patologiaRESUMO
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.