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Abstract: Mutations in C-terminal titin cause autosomal dominant tibial muscular dystrophy (TMD) as reported previously. Samples from 25 new families and 25 sporadic new distal myopathy cases were screened for titin mutations. Three novel mutations were discovered in two families from Spain and two families from France. Two mutations, g.292998delT and g.293376delA lead to frameshift and premature stop codons in the second last and the last titin gene (TTN) exons, Mex5 and Mex6, respectively. The third was a nonsense mutation g.293379C>T (p.Q33396X) in Mex6. Patients with the upstream Mex5 mutation showed a more severe phenotype with earlier onset implying a genotype–phenotype correlation. [Copyright &y& Elsevier]

An association study was carried out to examine the influence of methylmalonyl-CoA mutase ( MUT) polymorphisms on the susceptibility of a well-studied wild boar population from southern Spain to develop bovine tuberculosis (bTB). To this end, we examined polymorphisms at a closely linked dinucleotide microsatellite flanking exon 2 of the MUT gene in 37 wild boars with bTB and 36 non-infected individuals. The microsatellite showed low polymorphism in the studied population, with only three alleles ( MUTm- A, MUTm- B and MUTm- C) found, in contrast to the 11 alleles previously reported for domestic pigs. Our case–control study showed that the MUTm-B allele was associated with disease in a dominant pattern (odds ratio = 3.36; 95% CI = 1.05–10.72; P = 0.04), while the MUTm AA genotype appeared to have a protective effect against bTB infection (odds ratio = 4.33; 95% CI = 1.20–14.96; P = 0.02). Interestingly, infected wild boars heterozygous for MUTm AB are at an advantage (11-fold) to contain the systemic spread of the disease when compared to other genotypes, implying that a balanced polymorphism may be present in the population. These results strengthen previous observations regarding the importance of the MUT gene on bTB resistance in wild boars and indicate that polymorphisms at this locus will influence the risk of acquiring and maintaining bTB in the studied population. [ABSTRACT FROM AUTHOR]

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Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder caused by mutations in the SMN1 (survival motor neuron) gene. It is classified by age of onset and maximal motor milestones achieved in type I, II, and III (severe, intermediate, and mild form, respectively). Of 369 unrelated SMA patients who were investigated for homozygous deletions in the SMN1 gene, 18 patients (4.8%) revealed at least one copy of exon 7. A 4?bp deletion in exon 3 (c.399_402delAGAG) was detected in 15 patients from 10 families. This mutation was associated with a large spectrum of phenotypes from type I to asymptomatic patients. Five patients from two consanguineous families were homozygous for the mutation with diverse mild phenotypes. Determination of the SMN2 copy number showed that the presence of two or three copies generally correlated with a better evolution. RT?PCR studies of SMN transcripts in control and patients with the same SMN2 copy number showed that the full?length/?7 ratio is influenced by the SMN1 genotype although it seems independent of the SMN2 copy number. Moreover, protein analysis in these patients showed a reduction in SMN protein in compound heterozygous patients (c.399_402delAGAG/deletion) when compared with homozygous c.399_402delAGAG/c.399_402delAGAG patients. Microsatellite DNA markers flanking the SMA locus revealed the occurrence of the 4?bp deletion in the background of the same haplotype, suggesting that a single mutational event was involved in the 10 families. The geographic origins of ancestors point to a founder effect from the south and east of Spain. The c.399_402delAGAG, which is to date unique to the Spanish population, constitutes the most frequently found subtle mutation in SMA. Hum Mutat 22:136–143, 2003. © 2003 Wiley?Liss, Inc. [ABSTRACT FROM AUTHOR]

Hereditary non-syndromic sensorineural hearing loss (NSSHL) is a genetically highly heterogeneous group of disorders. Autosomal dominant forms account for up to 20% of cases. To date, 39 loci have been identified by linkage analysis of affected families that segregate NSSHL forms in the autosomal dominant mode (DFNA). Investigation of a large Spanish pedigree with autosomal dominant inheritance of bilateral and progressive NSSHL of postlingual onset excluded linkage to known DFNA loci and, in a subsequent genome-wide scan, the disorder locus was mapped to 3q28–29. A maximum two-point LOD score of 4.36 at θ=0 was obtained for marker D3S1601. Haplotype analysis placed the novel locus, DFNA44, within a 3-cM genetic interval defined by markers D3S1314 and D3S2418. Heteroduplex analysis and DNA sequencing of coding regions and exon/intron boundaries of two genes (CLDN16 and FGF12) in this interval did not reveal disease-causing mutations. [ABSTRACT FROM AUTHOR]

Background: A myocyte enhancer factor 2A (MEF2A) mutation that segregated with coronary artery disease/myocardial infarction (CAD/MI) in a large family has recently been described. Missense mutations in sporadic coronary artery disease patients were also reported. These data suggest that mutations in exons 7 and 11 of MEF2A cause CAD/MI, though the association was refuted by another study. Objective: To analyse the genetic variation of exons 7 and 11 in a large cohort of Spanish CAD/MI patients and controls. Methods and results: A rare polymorphism, P279L, was detected both in patients and controls. Carriers of the 279Leu allele had a threefold risk of suffering CAD/MI compared with controls (p = 0.009; odds ratio = 3.06 (95% confidence interval, 1.17 to 8.06)). In the controls the allele was found only in those under 50 years of age. Exon 11 showed a high degree of heterogeneity caused by a polyglutamine (CAG)n polymorphism, but no significant differences in genotype or allelic frequencies were found. Conclusions: The 279Leu allele appears to be a genetic risk factor for CAD/MI in the population studied. This effect could be the result of a reduced transcriptional activity on MEF2A with 279Leu. [ABSTRACT FROM AUTHOR]

Two new HLA class I alleles, HLA-A*11:01:01:04 and HLA-B*35:330, were characterized in a Spanish patient. [ABSTRACT FROM AUTHOR]

DRB1*04:98 shows four nucleotide changes regarding DRB1*04:01:01, resulting in two amino acids replacement at positions A73G and A74R. [ABSTRACT FROM AUTHOR]

The p.Ala204Thr mutation (exon 7) of the CLCNKB gene is a "founder" mutation that causes most of type III Bartter syndrome cases in Spain. We performed genetic analysis of the CLCNKB gene, which encodes for the chloride channel protein ClC-Kb, in a cohort of 26 affected patients from 23 families. The diagnostic algorithm was: first, detection of the p.Ala204Thr mutation; second, detecting large deletions or duplications by Multiplex Ligation-dependent Probe Amplification and Quantitative Multiplex PCR of Short Fluorescent Fragments; and third, sequencing of the coding and flanking regions of the whole CLCNKB gene. In our genetic diagnosis, 20 families presented with the p.Ala204Thr mutation. Of those, 15 patients (15 families) were homozygous (57.7% of overall patients). Another 8 patients (5 families) were compound heterozygous for the founder mutation together with a second one. Thus, 3 patients (2 siblings) presented with the c. -19-?_2053+? del deletion (comprising the entire gene); one patient carried the p.Val170Met mutation (exon 6); and 4 patients (3 siblings) presented with the novel p.Glu442Gly mutation (exon 14). On the other hand, another two patients carried two novel mutations in compound heterozygosis: one presented the p.Ile398_Thr401del mutation (exon 12) associated with the c. -19-?_2053+? del deletion, and the other one carried the c.1756+1G>A splice-site mutation (exon 16) as well as the already described p.Ala210Val change (exon 7). One case turned out to be negative in our genetic screening. In addition, 51 relatives were found to be heterozygous carriers of the described CLCNKB mutations. In conclusion, different mutations cause type III Bartter syndrome in Spain. The high prevalence of the p.Ala204Thr in Spanish families thus justifies an initial screen for this mutation. However, should it not be detected further investigation of the CLCNKB gene is warranted in clinically diagnosed families. [ABSTRACT FROM AUTHOR]