Carmen Nájera

Retinitis pigmentosa in Spain

Retinitis pigmentosa is a term commonly given to a group of inherited and progressive disorders which affect the photoreceptors of the retina. As part of an ongoing research programme throughout Spain, clinical, epide‐miological, and genetic studies have been carried out on these diseases. Here, we report the relative frequencies of the different genetic types in 503 non‐syndromic and 89 syndromic RP families of Spanish origin. The most frequent syndromic RP forms were Usher syndrome type 1 (20/ 89 families=30%) and Usher syndrome type 2 (44 families=49%). Among non‐syndromic RP forms, 12% were autosomal dominant, 39% autosomal recessive and 4% X‐linked. Forty‐one percent were isolated or simplex cases and in 4% the genetic type could not be established.

Identification of 14 novel mutations in the long isoform of USH2A in Spanish patients with Usher syndrome type II

Mutations in USH2A gene have been shown to be responsible for Usher syndrome type II, an autosomal recessive disorder characterised by hearing loss and retinitis pigmentosa. USH2A was firstly described as consisting of 21 exons, but 52 novel exons at the 3’ end of the gene were recently identified. In this report, a mutation analysis of the new 52 exons of USH2A gene was carried out in 32 unrelated patients in which both disease-causing mutations could not be found after the screening of the first 21 exons of the USH2A gene. On analysing the new 52 exons, fourteen novel mutations were identified in 14 out of the 32 cases studied, including 7 missense, 5 frameshift, 1 duplication and a putative splice-site mutation.

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 nonpathologic. Mutations were detected in 62 patients with USH (33.9%). According to the clinical classification of patients, pathologic variants were detected in 31.4% patients with USH1, 39.4% of with USH2, 22.2% with USH3 and 15.8% with unclassified Usher syndrome. Ninety-seven pathologic alleles were detected, corresponding to 26.5% of expected alleles. The USH2A mutations p.C3267R and p.T3571M were revealed as common in the Spanish population, and two major haplotypes linked to these mutations were observed. CONCLUSIONS The genotyping microarray is a robust, low-cost, rapid technique that is effective for the genetic study of patients with USH. However, it also indicates variants of unclear pathologic nature and detection failures have also been observed. Results must be confirmed by direct sequencing to avoid misdiagnosis, and continuous updates of the microarray should be performed to increase the efficiency and rate of detection of mutations.

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 syndrome, whereas the C759F mutation, regardless of being associated with the 2299delG mutation or not, was identified in cases with nonsyndromic RP, as well as in patients with RP associated with a variability of hearing impairment. The comparative analysis of both phenotypic and genotypic data supports the hypothesis that sensorineural hearing loss in patients with RP may depend on the nature and on the association of the USH2A allele variants present.

Epidemiology of Usher Syndrome in Valencia and Spain

Objective: 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. Methods: Otological, ophthalmological and genetic studies were performed in 89 US patients from 46 families and subjected to statistical and segregation analysis. Results: 41.6% of them suffered US type I, 46.1% type II, and in 12.3% the classification remains unclear. The estimated prevalence for the Province of Valencia was 4.2/100,000. There was a notable excess of male-only affected multiplex sibships in our sample that could be attributable to an X-linked inheritance. Conclusions: The number of families with USI type was similar to that of families with USII type. The estimated prevalence for the Province of Valencia is in agreement with other reports in which the estimate for the prevalence of US ranges from 1.8 to 6.2/100,000.

MYO7A mutation screening in Usher syndrome type I patients from diverse origins

Usher syndrome (USH) (OMIM 276901) is an autosomal recessive disorder characterised by hearing impairment associated with retinitis pigmentosa and in some cases vestibular dysfunction. This disease accounts for approximately 50% of individuals with combined deafness and blindness in developed countries. The estimated prevalence of USH ranges from 3.8 to 6.2/100 000.1–3 Phenotypically, three clinical types of Usher syndrome have been defined according to the severity of hearing impairment, age of retinitis pigmentosa onset and the presence or absence of vestibular response. Usher syndrome type I (USH1) is the most serious type, characterised by severe to profound congenital sensorineural hearing loss, balance deficiency and prepubertal onset of retinitis pigmentosa leading to blindness. USH2 is characterised by moderate to severe hearing impairment, normal vestibular function and later onset of retinal degeneration than USH1. USH3 displays progressive hearing loss, retinitis pigmentosa and variable vestibular phenotype. Six loci for USH1 (USH1B–USH1G) have been mapped and, to date, five genes have been identified.4,5 The MYO7A gene was found to be responsible for USH1B6 and is the most common subtype of USH1, accounting for approximately 50% of cases.7–9 Defects in MYO7A also cause autosomal dominant non-syndromic sensorineural hearing impairment (DFNA11) (MIM 601317),10 autosomal recessive deafness (DFNB2) (MIM 600060)11,12 as well as atypical types of Usher syndrome which are clinically similar to USH3.13 The MYO7A gene has 49 exons, of which 48 are coding, and spans approximately 87 kb of genomic sequence on chromosome 11q13.5. The encoded protein is an unconventional myosin, the myosin VIIA,14 predicted to consist of 2215 amino acids and has a molecular mass of 254 kDa. This protein contains three typical domains: the N terminal head or motor; the neck or regulatory domain consisting of five IQ motifs; and the tail …

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 for mutations in clarin‐1 gene among our series of Usher syndrome Spanish patients. Clarin‐1 has been found to be responsible for the disease in only two families: the first one is a previously reported family homozygous for Y63X mutation and the second one, described here, is homozygous for C40G. This accounts for 1.7% of Usher syndrome Spanish families. It is noticeable that, whereas C40G family is clinically compatible with Usher syndrome type III due to the progression of the hearing loss, Y63X family could be diagnosed as Usher syndrome type I because the hearing impairment is profound and stable. Thus, we consider that the progression of hearing loss is not the definitive key parameter to distinguish Usher syndrome type III from Usher syndrome type I and Usher syndrome type II.

The USH2A c.2299delG mutation: dating its common origin in a Southern European population

Usher syndrome type II is the most common form of Usher syndrome. USH2A is the main responsible gene of the three known to be disease causing. It encodes two isoforms of the protein usherin. This protein is part of an interactome that has an essential role in the development and function of inner ear hair cells and photoreceptors. The gene contains 72 exons spanning over a region of 800 kb. Although numerous mutations have been described, the c.2299delG mutation is the most prevalent in several populations. Its ancestral origin was previously suggested after the identification of a common core haplotype restricted to 250 kb in the 5′ region that encodes the short usherin isoform. By extending the haplotype analysis over the 800 kb region of the USH2A gene with a total of 14 intragenic single nucleotide polymorphisms, we have been able to define 10 different c.2299delG haplotypes, showing high variability but preserving the previously described core haplotype. An exhaustive c.2299delG/control haplotype study suggests that the major source of variability in the USH2A gene is recombination. Furthermore, we have evidenced twice the amount of recombination hotspots located in the 500 kb region that covers the 3′ end of the gene, explaining the higher variability observed in this region when compared with the 250 kb of the 5′ region. Our data confirm the common ancestral origin of the c.2299delG mutation.

FOXP2 polymorphisms in patients with schizophrenia

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 controls. No significant differences were found between individual controls and patients for the two analysed polymorphisms. CONCLUSIONS This study would not support a possible role of the two FOXP2 analyzed polymorphisms in the vulnerability to schizophrenia.

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.