Mutation spectrum of EYS in Spanish patients with autosomal recessive retinitis pigmentosa

29 páginas, 4 figuras, 3 tablas.-- et al.Retinitis pigmentosa (RP) is a heterogeneous group of inherited retinal dystrophies characterised ultimately by the loss of photoreceptor cells. We have recently identified a new gene (EYS) encoding an ortholog of Drosophila spacemaker (spam) as a commonly mutated gene in autosomal recessive RP. In the present study, we report the identification of 73 sequence variations in EYS, of which 28 are novel. Of these, 42.9% (12/28) are very likely pathogenic, 17.9% (5/28) are possibly pathogenic, whereas 39.3% (11/28) are SNPs. In addition, we have detected 3 pathogenic changes previously reported in other populations. We are also presenting the characterisation of EYS homologues in different species, and a detailed analysis of the EYS domains, with the identification of an interesting novel feature: a putative coiled-coil domain. Majority of the mutations in the arRP patients have been found within the domain structures of EYS. The minimum observed prevalence of distinct EYS mutations in our group of patients is of 15.9% (15/94), confirming a major involvement of EYS in the pathogenesis of arRP in the Spanish population. Along with the detection of three recurrent mutations in Caucasian population, our hypothesis of EYS being the first prevalent gene in arRP has been reinforced in the present study.This study was funded by PN de I+D+I 2008- 2011, Instituto de Salud Carlos III (ISCIII) -Subdirección General de Evaluación y Fomento de la Investigación, Fondo de Investigación Sanitaria (PI081131), Spain; Consejería de Salud (PI-0334/2007), Consejería de Innovación, Ciencia y Empresa (PI08-CTS-03687), Junta de Andalucía, Spain; El Centro de Investigación Biomédica en Red de Enfermedades Raras is an initiative of the Instituto de Salud Carlos III. J.I. P. was supported by Fondo de Investigación Sanitaria and M. G-dP by Consejería de Innovación, Ciencia y Empresa, Junta de Andalucía, Spain. The research of K.W.L. was funded by the Stichting Wetenschappelijk Onderzoek Oogziekenhuis Prof. Dr. H.J. Flieringa, Rotterdam. Contract grant sponsor: Fondo de Investigación Sanitaria, Spain; Consejería de Salud; Consejería de Innovación, Ciencia y Empresa; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER). Contract grant number: PI081131, PI-0334/2007, PI08-CTS-03687Peer reviewe

Copy-number variations in EYS: a significant event in the appearance of arRP

Creative Commons Attribution Non-Commercial No Derivatives License.[Purpose]: Autosomal recessive retinitis pigmentosa (arRP) has recently been associated with mutations in a novel gene, EYS, which is a major gene for this disease. All published mutations so far are based on conventional PCR and are not adequate to identify midsized DNA rearrangements. This study was conducted to establish the prevalence of copy-number variations (CNVs) in the EYS gene in a cohort of arRP patients, including individuals in whom only one pathogenic change was detected by PCR-based sequencing.[Methods]: A multiple ligation-dependent probe amplification (MLPA) was used for the molecular genetic analyses of CNVs by a novel EYS-specific kit. PCR-based direct sequencing was used in families where a pathogenic deletion or duplication was identified in one allele. Bioinformatics analyses was undertaken to study the effect of the mutations on protein structure and function.[Results]: Six novel pathogenic CNVs were identified. Also, the presence of four midsized deletions was confirmed in patients previously identified. Midsized genomic rearrangements in EYS are disease causing in ∼4% of the families with no reported mutations and constitute the second pathogenic variation in ∼15% of cases where a mutation has been detected by direct sequencing.[Conclusions]: This is the first report of a systematic CNV screening of EYS gene in a cohort of arRP patients. Results suggest that midsized genomic rearrangements in EYS gene would be a common event in the appearance of RP phenotype. An efficient and cost-effective strategy validating a novel MLPA kit as a complementary diagnostic method for EYS pathogenic evaluation has been demonstrated.Supported by PN de IDI 2008–2011, Instituto de Salud Carlos III (ISCIII), Subdirección General de Evaluación y Fomento de la Investigación, Fondo de Investigación Sanitaria (PI081131), Spain; Consejería de Innovación, Ciencia y Empresa (PI08-CTS-03687), Junta de Andalucía, Spain; The Foundation Fighting Blindness (USA). The British Retinitis Pigmentosa Society. El Centro de Investigación Biomédica en Red de Enfermedades Raras is an initiative of the Instituto de Salud Carlos III. JIP was supported by Fondo de Investigación Sanitaria, and MG-DP by Consejería de Innovación, Ciencia y Empresa, Junta de Andalucía, Spain.Peer Reviewe

Somatic mosaicism for Y120X mutation in the MECP2 gene causes atypical Rett syndrome in a male

Supplementary data associated with this article can be found, in the online version, at doi:10.1016/ j.braindev.2010.09.012Rett Syndrome (RS; MIM_312750) is a severe and progressive neurodevelopmental disorder affecting principally females. Mutations in X-Linked MECP2 gene (methyl CpG-binding protein 2; MIM_300005) have been reported as being the major cause of RS. Mutations in this gene have been described as cause of wide spectrum of neurological disorders and mental retardation in males. In some cases, mutations in MECP2 in males produce clinical picture similar to RS. Here we report the identification of the novel truncating mutation Y120X in a 4-year-old child with atypical RS phenotype. Chromosome analysis showed a normal karyotype, and blood DNA and tissue DNA analysis reveal a mosaic for the mutation. Patient's mother DNA analysis showed that this is a de novo mutation, that has never been described before in any female or male case of RS. © 2010 The Japanese Society of Child Neurology.The CIBER de Enfermedades Raras is an initiative of the ISCIII. J.I.P. was supported by Fondo de Investigación Sanitaria.Peer Reviewe