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

Aller, Elena; Larrieu, Lise; Jaijo, Teresa; Baux, David; Espinós, Carmen; Gónzález-Candelas, Fernando; Nájera, Carmén; Palau, Francesc; Claustres, Mireille; Roux, Anne‐Françoise; Millán, José María

doi:10.1038/ejhg.2010.14

Cited by 48 publications

(44 citation statements)

References 31 publications

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“…Recent studies on Irish population history suggested that a large proportion of Irish population was originated from northern Spain. Interestingly, the USH2A haplotype identified in our cohort is also found to be widespread in Spanish RP and Usher patients (Najera et al 2002; Aller et al 2010), which supports the close link between Irish and Spanish population.…”

Section: Discussionsupporting

confidence: 86%

“…As an example, the well-known c.2299delG, p.(Glu767Serfs) mutation in USH2A is frequently found in European patients. This mutation accounts for 47.5 % of USH2A alleles in Denmark (Dreyer et al 2008), while the allelic frequency is 31 % in the Netherlands (Pennings et al 2004) and 10 % in France (Aller et al 2010). The mutation frequency may become common as a result of the founder effect and may change due to genetic drift.…”

Section: Introductionmentioning

confidence: 99%

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Next-generation sequencing-based molecular diagnosis of 82 retinitis pigmentosa probands from Northern Ireland

Zhao

Wang

et al. 2014

Hum Genet

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Retinitis pigmentosa (RP) is a group of inherited retinal disorders characterized by progressive photoreceptor degeneration. An accurate molecular diagnosis is essential for disease characterization and clinical prognoses. A retinal capture panel that enriches 186 known retinal disease genes, including 55 known RP genes, was developed. Targeted next-generation sequencing was performed for a cohort of 82 unrelated RP cases from Northern Ireland, including 46 simplex cases and 36 familial cases. Disease-causing mutations were identified in 49 probands, including 28 simplex cases and 21 familial cases, achieving a solving rate of 60 %. In total, 65 pathogenic mutations were found, and 29 of these were novel. Interestingly, the molecular information of 12 probands was neither consistent with their initial inheritance pattern nor clinical diagnosis. Further clinical reassessment resulted in a refinement of the clinical diagnosis in 11 patients. This is the first study to apply next-generation sequencing-based, comprehensive molecular diagnoses to a large number of RP probands from Northern Ireland. Our study shows that molecular information can aid clinical diagnosis, potentially changing treatment options, current family counseling and management.

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Section: Discussionsupporting

confidence: 86%

Section: Introductionmentioning

confidence: 99%

Next-generation sequencing-based molecular diagnosis of 82 retinitis pigmentosa probands from Northern Ireland

Zhao

Wang

et al. 2014

Hum Genet

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“…Despite this, it is plausible to hypothesize that the CTH c.200C>T change happened in a Neolithic population from Central Europe and by means of migration fluxes, this population entered Spain at the Pyrenees, consistent with the archaeological findings (11). A founder mutation USH2A c.2299delG involved in a rare disease, the Usher syndrome type 2A (MIM 276901), has been dated as happening 200-500 generations ago (12). In this case a geographic cline is observed: the USH2A c.2299delG mutation is more frequent in North Europe and less frequent in Mediterranean countries.…”

Section: Discussionmentioning

confidence: 71%

Ancient origin of the CTH alelle carrying the c.200C>T (p.T67I) variant in patients with cystathioninuria

et al. 2010

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Hereditary cystathioninuria is due to mutations in the CTH gene that encodes for cystathionase, a pyridoxal-5'-phosphate (PLP) dependent enzyme. To date, mutations in this gene have been described in 10 unrelated cystathioninuric patients. Enzyme assays have showed that mutated cystathionase exhibits lower activity than controls. As cystathioninuria is usually accompanied by a wide variety of symptoms, it has been questioned whether it is a disease or just a biochemical finding not associated with the clinical picture of these patients. This is the first report of Spanish patients with cystathioninuria and mild to severe neurological symptoms in childhood. After oral pyridoxine therapy biochemical parameters have normalized but clinical amelioration was not evident. All patients were homozygotes for the c.200C>T (p.T67I) variant which is the most prevalent inactivating mutation in the CTH gene. To further investigate the history of the alleles carrying the c.200C>T transition in Europe, we also constructed the haplotypes on the CTH locus in our Spanish patients as well as in a clinical series of cystathioninuric patients from the Czech Republic harboring the same nucleotide change. We suggest that the CTH p.T67I substitution could have an ancient common origin, which probably occurred in the Neolithic Era and spread throughout Europe.

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“…A similar study performed in 39 Italian patients, using a chip for the most frequent variants identified in Caucasians, revealed USH2A causative mutations in 15.4% of cases (Vozzi et al, 2011). Among the mutations already associated with Usher type II, the c.2299del variant was found in 25% of patients (2 of 8); this variant is the most common mutation detected in Europe and the USA and may have a South-European origin (Eudy et al, 1998;Aller et al, 2010). The c.2299del frameshift variant (p.Glu767Serfs*21) and the nonsense mutation c.187C>T (p.Arg63*) identified in our patients were found to be the most frequently observed mutations in the Italian population and are described in the present study and in Vozzi et al (2011).…”

Section: Discussionmentioning

confidence: 99%

“…This is the first phase our screening, which did not include direct sequencing of exons 22-72 or detection of gross deletions. This protocol is based on previous studies (Aller et al, 2010;McGee et al, 2010). Analysis of the longer isoform of USH2A clearly increases the detection rate, and a second screening step is currently underway to complete the genetic testing of USH2A patients.…”

Section: Discussionmentioning

confidence: 99%

Syndromic and non-syndromic forms of retinitis pigmentosa: a comprehensive Italian clinical and molecular study reveals new mutations

Pierrottet¹,

Zuntini²,

Digiuni³

et al. 2014

Genet. Mol. Res.

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ABSTRACT. Mutations in more than 60 different genes have been associated with non-syndromic and syndromic retinitis pigmentosa (RP), a heterogeneous group of inherited retinal dystrophies. To increase the understanding of the molecular epidemiology of the disease in Italy, we analyzed 56 patients with syndromic and non-syndromic forms of RP attending the Retinitis Pigmentosa Center of San Paolo Hospital (Milan, Italy). Patients underwent detailed clinical examination. Genomic DNA isolated from peripheral blood samples was screened for mutations in different genes according to RP form by direct sequencing analysis. The impact of novel missense mutations on protein functions was predicted by in silico analysis and protein sequence alignment. Cosegregation analysis was performed between available family members. Forty-one of the 56 probands analyzed had non-syndromic and 15 had syndromic RP forms. Putative disease-causing mutations were identified in 19 of 56 unrelated RP probands. Mutation screening identified a total of 22 different heterozygous variants. Notably, 12 of these putative pathogenic mutations have not been previously reported. New variants were found to be located on the USH2A, RPGR, EYS, and RHO genes. All 3 new variants detected in X-linked RP probands were confirmed in other affected family members. We found a positivity rate of 24.4% and 60% for probands with non-syndromic and syndromic RP, respectively. This is the first report of RPGR X-linked RP proband-ORF15 mutations in Italian patients with X-linked (XL)-RP. In addition, this is the first report of data regarding the association between EYS mutations and non-syndromic RP forms in the Italian population.

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

Cited by 48 publications

References 31 publications

Next-generation sequencing-based molecular diagnosis of 82 retinitis pigmentosa probands from Northern Ireland

Next-generation sequencing-based molecular diagnosis of 82 retinitis pigmentosa probands from Northern Ireland

Ancient origin of the CTH alelle carrying the c.200C>T (p.T67I) variant in patients with cystathioninuria

Syndromic and non-syndromic forms of retinitis pigmentosa: a comprehensive Italian clinical and molecular study reveals new mutations

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