Genetic analysis of 2299delG and C759F mutations (USH2A) in patients with visual and/or auditory impairments

The most common mutation in the USH2A gene (Usherin), 2299delG, causes both typical Usher (USH) syndrome type II and atypical USH syndrome, two autosomal recessive disorders, characterised by moderate to severe sensorineural hearing loss and retinitis pigmentosa (RP). Furthermore, the C759F mutation in the USH2A gene has been described in 4.5% of patients with nonsyndromic recessive RP. We have investigated the presence of the 2299delG and/or the C759F mutations in 191 unrelated Spanish patients with different syndromic and nonsyndromic retinal diseases, or with nonsyndromic hearing impairment. The 2299delG mutation was observed in patients with clinical signs of USHII or of atypical USH sy…

Allelic age of the USH2A c.2299delG mutation

24 p., figuras y bibliografía

Identification of three novel mutations in the MYO7A gene

Three new mutations in the myosin VIIA gene involved in the pathogenesis of Usher syndrome type Ib are reported. These mutations are K1080X in exon 25, E1170K in exon 28, and Y1719C in exon 37. It is presumed that these mutations are involved in the Usher syndrome Ib phenotype. Hum Mutat 14:181, 1999. Copyright 1999 Wiley-Liss, Inc.

Diagnóstico temprano del retinoblastoma: importancia de la búsqueda de mutaciones en el gen RB1

Fundamento El retinoblastoma, cancer intraocular infantil mas frecuente, se presenta como esporadico (unilateral o bilateral) o afectando a varios miembros de una familia. En los casos hereditarios aparece por una mutacion germinal transmitida o surgida de novo, mientras que en los no hereditarios se debe a dos mutaciones somaticas en una celula de la retina. El presente trabajo se planteo con objeto de analizar desde el punto de vista genetico el gran numero de familias con algun miembro afectado de retinoblastoma, recopiladas en los ultimos anos, para ahondar en los mecanismos moleculares que inciden en este proceso patologico y ofrecerles consejo genetico. Pacientes y metodo Se han anali…

Genetics of retinoblastoma: A study

Abstract We have analyzed 43 families with either familial retinoblastoma (RB) (four kindreds), bilateral sporadic RB (10 individuals), or unilateral sporadic RB (29 individuals). Genetic studies focused on karyotype analysis, loss of heterozygosity of intragenic polymorphisms, and search for point mutations. We have been able to identify the genetic defect underlying the disease in eight cases. Deletions have been found in three patients with sporadic RB, two bilateral in one of which karyotyping had previously detected an interstitial deletion of chromosome 13 affecting (q13–q31) and one unilateral. Five different point mutations were responsible for three cases of bilateral sporadic RB, …

Impact of the AHI1 gene on the vulnerability to schizophrenia: a case-control association study.

Background: The Abelson helper integration-1 (AHI1) gene is required for both cerebellar and cortical development in humans. While the accelerated evolution of AHI1 in the human lineage indicates a role in cognitive (dys)function, a linkage scan in large pedigrees identified AHI1 as a positional candidate for schizophrenia. To further investigate the contribution of AHI1 to the susceptibility of schizophrenia, we evaluated the effect of AHI1 variation on the vulnerability to psychosis in two samples from Spain and Germany. Methodology/Principal Findings: 29 single-nucleotide polymorphisms (SNPs) located in a genomic region including the AHI1 gene were genotyped in two samples from Spain (28…

Polymorphism of Alcohol Dehydrogenase Genes in Alcoholic and Nonalcoholic Individuals from Valencia (Spain)

Polymorphisms in the two variable ADH loci (ADH2 and ADH3) were analyzed in two groups (alcoholics and nonalcoholics) from a Spanish population. The frequencies were similar to those reported for other Causcasian groups. ADH2-1 and ADH3-1 genotypes were more frequent in alcoholics than in nonalcoholics, but the differences were not significant.

An autosomal dominant retinitis pigmentosa family with close linkage to D7S480 on 7q.

Retinitis pigmentosa is the most prevalent inherited disorder of the retina. It can be autosomal dominant (adRP), autosomal recessive (arRP) or X-linked (XLRP). A form of adRP mapping to chromosome 7q was reported in a large Spanish pedigree. We have typed DNA from the members of another Spanish family for polymorphic markers from the known candidate genes. Positive lod scores were obtained only for the markers located on 7q31-35, giving a maximum lod score of 2.98 (3.01 by multipoint analysis) at theta = 0.00 for D7S480. A brief clinical evaluation is given.

Mutation screening of USH3 gene (clarin-1) in Spanish patients with Usher syndrome: low prevalence and phenotypic variability

Usher syndrome type III is an autosomal recessive disorder clinically characterized by the association of retinitis pigmentosa (RP), variable presence of vestibular dysfunction and progressive hearing loss, being the progression of the hearing impairment the critical parameter classically used to distinguish this form from Usher syndrome type I and Usher syndrome type II. Usher syndrome type III clinical subtype is the rarest form of Usher syndrome in Spain, accounting only for 6% of all Usher syndrome Spanish cases. The gene responsible for Usher syndrome type III is named clarin-1 and it is thought to be involved in hair cell and photoreceptor cell synapses. Here, we report a screening fo…

Serotonin transporter gene polymorphism (5-HTTLPR) and emotional response to auditory hallucinations in schizophrenia

The serotonin transporter (5-HTT) has a crucial function in the regulation of serotonin (5-HT) reuptake in presynaptic neurons. 5-HT is a major modulator of emotional behaviour and circadian rhythms. In addition to its neurotransmitter role, it is also an important regulator of morphogenetic activities during early brain development as well as during adult neurogenesis and plasticity (Murphy et al., 2001).

El síndrome de Usher: un ejemplo de heterogeneidad genética

El sindrome de Usher (USH) comprende una serie de enfermedades hereditarias caracterizadas por sordera bilateral neurosensorial congenita y perdida progresiva de vision debida a retinosis pigmentaria. Clinicamente se diferencian 3 subtipos, USH1, USH2 y USH3, cada uno de los cuales es geneticamente heterogeneo. Hasta 11 genes diferentes participan en este proceso, la mayoria de ellos implicados tambien en patologias auditivas o visuales no sindromicas. El gen MYO7A es responsable del 75% de los casos USH1 y el gen Usherina del 82% de los casos USH2A. Todos los productos proteicos interaccionan entre si, se expresan en coclea y retina y desempenan un papel esencial en la homeostasis de los e…

El asesoramiento genético en los déficits visuales y auditivos

espanolObjetivo: Las enfermedades hereditarias que afectan a la retina y la audicion presentan una amplia heterogeneidad clinica y genetica. Durante la pasada decada se han producido importantes avances en el conocimiento de la patogenia molecular de estas enfermedades y, actualmente, mas de 200 genes y loci estan implicados en enfermedades de la retina y mas de 60 son responsables de perdida de audicion. Metodo: El estudio genetico molecular es crucial para confirmar el diagnostico clinico, permite, en ocasiones, conocer el pronostico de la enfermedad, un consejo genetico y reproductivo adecuado y permite la posibilidad de crear grupos de pacientes geneticamente homogeneos para futuros ens…

A possible association between the CCK-AR gene and persistent auditory hallucinations in schizophrenia.

AbstractRecent studies have suggested that DNA variations in the CCK-AR gene might predispose individuals to schizophrenia and particularly to auditory hallucinations (AH). The aim of this study is to assess the association between AH, using a specific scale for AH in schizophrenia (PSYRATS), and the CCK-AR polymorphism at 779 in a Spanish sample. A total of 105 DSM-IV schizophrenic patients with AH and 93 unrelated controls were studied. Twenty-two patients were considered as persistent auditory hallucinators, which showed similar clinical and demographic characteristic than patients with episodic AH, but with the exception of the PSYRATS values. The persistent AH group showed an excess of…

Gly114Asp mutation of rhodopsin in autosomal dominant retinitis pigmentosa

Two autosomal dominant retinitis pigmentosa families of different origin were screened for rhodopsin mutations using the method of single strand conformation polymorphism and direct sequencing. We found a CGG-CAG substitution in codon 114 of rhodopsin in both families. This change predicted the replacement of a glycine by an aspartic acid and suggested that this change is the cause of the disease in these families.

Estudio genético molecular del síndrome de Usher en España

Usher syndrome (USH) associates deafness and retinitis pigmentosa (RP). It is a disease both clinically and genetically heterogeneous. It is inherited as an autosomal recessive trait and its prevalence makes it the most frequent association of hearing loss and RP. Clinically Usher syndrome is divided into type I (USH1), II (USH2) and III (USH3), according to the severity of hearing loss, age of onset of RP and the existence or not of vestibular dysfunction. There are at least 7 different localizations for USH1 and 5 genes have been identified. For USH2, 3 loci and 2 genes have been reported and USH3 is due to Clarin-1 gene. Our aim is to perform a clinical and genetic characterization of al…

Linkage analysis in Usher syndrome type I (USH1) families from Spain.

Usher syndrome (USH) is an autosomal recessive hereditary disorder characterised by congenital sensorineural hearing loss and gradual visual impairment secondary to retinitis pigmentosa (RP). The disorder is clinically and genetically heterogeneous. With regard to Usher type I (USH1), several subtypes have been described, the most frequent being USH1B located on chromosome 11q13.5. Of 18 USH1 families studied by linkage analysis, 12 (67%) showed significant lod score values for locus D11S527 (Zmax=14.032, theta=0.000) situated on chromosome 11q. Our findings suggest considerable genetic heterogeneity in the Spanish USH1 population. It is important to note that one of our families linked to …

Detection of a novel Cys628STOP mutation of the myosin VIIA gene in Usher syndrome type Ib.

A Spanish family with three Usher I syndrome-affected members was linked to markers located on chromosome 11q. A search for mutations on the myosin VIIA gene revealed a novel mutation (Cys628STOP) on exon 16 segregating with the disorder in a homozygous state. This nonsense mutation could be responsible for the disease since it leads to a truncated protein that presumably has no function.

Screening of the USH1G gene among Spanish patients with Usher syndrome. Lack of mutations and evidence of a minor role in the pathogenesis of the syndrome.

The Usher syndrome (USH) is an autosomal recessive hereditary disorder characterized by the association of sensorineural hearing loss, retinitis pigmentosa (RP) and, in some cases, vestibular dysfunction. The USH1G gene, encoding SANS, has been found to cause both Usher syndrome type I and atypical Usher syndrome. 109 Spanish unrelated patients suffering from Usher syndrome type I, type II, type III and unclassified Usher syndrome were screened for mutations in this gene, but only eight different changes without a clear pathogenic effect have been detected. Based on these results as well as previous studies in other populations where mutational analysis of this gene has been carried out, on…

Attenuation of disease phenotype through alternative translation initiation in low-penetrance retinoblastoma

Hereditary predisposition to retinoblastoma (RB) is caused by germline mutations in the retinoblastoma 1 (RB1) gene and transmits as an autosomal dominant trait. In the majority of cases disease develops in greater than 90% of carriers. However, reduced penetrance with a large portion of disease-free carrier is seen in some families. Unambiguous identification of the predisposing mutation in these families is important for accurate risk prediction in relatives and their genetic counseling but also provides conceptual information regarding the relationship between the RB1 genotype and the disease phenotype. In this study we report a novel mutation detected in 10 individuals of an extended fa…

Mutation profile of the MYO7A gene in Spanish patients with Usher syndrome type I.

Usher syndrome type I is the most severe form of Usher syndrome. It is an autosomal recessive disorder characterized by profound congenital sensorineural deafness, retinitis pigmentosa, and vestibular abnormalities. Mutations in the myosin VIIA gene (MYO7A) are responsible for Usher syndrome type 1B (USH1B). This gene is thought to bear greatest responsibility for USH1 and, depending on the study, has been reported to account for between 24% and 59% of USH1 cases. In this report a mutation screening of the MYO7A gene was carried out in a series of 48 unrelated USH1 families using single strand conformation polymorphism analysis (SSCP) and direct sequencing of those fragments showed an abnor…

Epidemiology of Usher Syndrome in Valencia and Spain

<b>Objective:</b> To obtain epidemiological data on the prevalence of the different types of Usher syndrome (US) in Spain, since these data were missing; to estimate the proportion of sporadic cases among simplex families, and calculate the prevalence of the Usher syndrome in a homogeneous population from Eastern Spain (3,875,234 inhabitants) that is representative of the Spanish population. <b>Methods:</b> Otological, ophthalmological and genetic studies were performed in 89 US patients from 46 families and subjected to statistical and segregation analysis. <b>Results:</b> 41.6% of them suffered US type I, 46.1% type II, and in 12.3% the classification r…

FOXP2 polymorphisms in patients with schizophrenia.

Abstract Background FOXP2 was described as the first gene involved in our ability to acquire spoken language. The main objective of this study was to compare the distribution of FOXP2 gene polymorphisms between patients with schizophrenia and healthy controls. Methods Two FOXP2 polymorphisms, Intron3a and SNP 923875, and the G→A transition in exon 14 were analysed in 149 patients with schizophrenia and schizoaffective disorders according to DSM-IV, as well as in 137 controls. All the patients showed a history of auditory hallucinations. Results The transition G→A at exon 14, detected in all the affected members in KE family, was not found in any of the analyzed samples from patients or cont…

Epidemiology of retinitis pigmentosa in the valencian community (Spain)

The purposes of this study are to determine the frequencies of the different genetic forms of retinitis pigmentosa and to perform segregation analysis in the different genetic subtypes. Retinitis pigmentosa was diagnosed in 263 persons from 132 families. The frequency of the autosomal recessive type was the highest (31.8%) while the X-linked type was very rare (1.5%). The frequency of autosomal dominant type was 14.4% and the simplex cases constituted half of the total cases of RP registered in our community. In conclusion, in our population the high proportion of simplex cases and the low number of X-linked families are noticeable. The result of segregation analysis showed good agreement w…

Functional analysis of splicing mutations in MYO7A and USH2A genes.

Usher syndrome is defined by the association of sensorineural hearing loss, retinitis pigmentosa and variable vestibular dysfunction. Many disease-causative mutations have been identified in MYO7A and USH2A genes, which play a major role in Usher syndrome type I and type II, respectively. The pathogenic nature of mutations that lead to premature stop codons is not questioned; nevertheless, additional studies are needed to verify the pathogenicity of some changes such as those putatively involved in the splice process. Five putative splice-site variants were detected in our cohort of patients: c.2283-1G>T and c.5856G>A in MYO7A and c.1841-2A>G, c.2167+5G>A and c.5298+1G>C in the USH2A gene. …

A novel constitutional mutation affecting splicing of retinoblastoma tumor suppressor gene intron 23 causes partial loss of pRB activity.

Hereditary predisposition to retinoblastoma is caused by germ line mutations in the RB1 gene. Genetic counseling of affected individuals and accurate risk prediction for their families requires identification of the disease causing mutation. Furthermore, the nature of a mutation can determine genetic penetrance, disease presentation and prognosis. We describe, and functionally characterize here, a novel mutant allele of RB1 present in the germ line of a patient with sporadic bilateral retinoblastoma. The mutation generates an operational splice acceptor site resulting in a predicted protein product with loss of 81 amino acids from its carboxy terminus. We demonstrate that the aberrantly spl…

The microcephaly ASPM gene and schizophrenia: A preliminary study

Genetic location and biochemical characterization of eye-colour mutants from natural populations of Drosophila melanogaster

From six captures of Drosophila melanogaster carried out in three different habitats (cellar, vineyard, and pinewood) in two different seasons of the year (spring and autumn), 60 eye-colour mutations were isolated, which were reduced to 29 loci by means of allelism tests within and between populations. Forty-five of these mutations were analyzed genetically and biochemically; of these 33 turned out to be previously described mutants and mapped to a total of 17 loci. Twelve new mutants were discovered and they mapped to 12 new loci, distributed on chromosomes X, II, and III. The eye-colour mutants show large effects on the red and brown pigments. The high variability of the eye-colour loci …

Microarray-based mutation analysis of 183 Spanish families with Usher syndrome.

PURPOSE. The purpose of this study was to test the ability of the genotyping microarray for Usher syndrome (USH) to identify the mutations responsible for the disease in a cohort of 183 patients with USH. METHODS. DNA from 183 patients with Usher syndrome from the Spanish population was analyzed using a genotyping microarray containing 429 previously identified disease-associated variants in eight USH genes. Mutations detected by the array were confirmed by direct sequencing. Haplotype analysis was also performed in families carrying common Spanish mutations. RESULTS. The genotyping microarray identified 43 different variants, divided into 32 disease causative and 11 probably non-pathologic…

Mutations in Myosin VIIA (MYO7A) and Usherin (USH2A) in Spanish patients with usher syndrome types I and II, respectively

Usher syndrome is an autosomal recessive disorder characterized by congenital hearing impairment and retinitis pigmentosa. Three clinical types are known (USH1, USH2 and USH3), and there is an extensive genetic heterogeneity, with at least ten genes implicated. The most frequently mutated genes are MYO7A, which causes USH1B, and usherin, which causes USH2A. We carried out a mutation analysis of these two genes in the Spanish population. Analysis of the MYO7A gene in patients from 30 USH1 families and sporadic cases identified 32% of disease alleles, with mutation Q821X being the most frequent. Most of the remaining variants are private mutations. With regard to USH2, mutation 2299delG was d…

Retinoblastoma: implicaciones del estudio genético-molecular