Origin of the myotonic dystrophy type 1 mutation in Mexican population and influence of Amerindian ancestry on CTG repeat allelic distribution.

Myotonic dystrophy type 1 is caused by expansion of a CTG trinucleotide repeat situated in the DMPK gene. Worldwide genetic studies suggest a single or limited number of mutational events cause the disease. However, distribution of CTG alleles and disease incidence varies among ethnicities. Due to the great ethnic diversity of the Mexican population, the present study was aimed at analyzing the impact of different lineages in shaping the CTG-repeat allelic distribution in the contemporary Mexican-Mestizo population as well as to shed light on the DM1 ancestral origin. Distribution of CTG-repeat alleles was similar among Mestizo and Amerindian subpopulations with (CTG)11-13 being the most frequent alleles in both groups, which implies that Mexican-Mestizo allelic distribution has been modeled by Amerindian ancestry. We diagnosed a relatively high number of cases, consistent with the high frequency of large-normal alleles found in Mexican subpopulations. Haplotype analysis using various polymorphic-markers in proximity to DMPK gene indicates that a single founder mutation originates myotonic dystrophy type 1 in Mexico; however, Y-STR haplogroups data and the presence of pre-mutated and large normal alleles in Amerindians support the hypothesis that both European and Amerindian ancestral chromosomes might have introduced the disease to the Mexican population, which was further disseminated through mestizaje.

[Genetic Variability and Structure of SNP Haplotypes in the DMPK Gene in Yakuts and Other Ethnic Groups of Northern Eurasia in Relation to Myotonic Dystrophy].

The genetic variability of the DMPK locus has been studied in relation to six SNP markers (rs2070736, rs572634, rs1799894, rs527221, rs915915, and rs10415988) in Yakuts with myotonic dystrophy (MD) in the Yakut population and in populations of northern Eurasia. Significant differences were observed in the allele frequencies between patients and a population sample of Yakuts for three SNP loci (rs915915, rs1799894, and rs10415988) associated with a high chance of disease manifestation. The odds ratios (OR) of MD development in representatives of the Yakut population for these three loci were 2.59 (95% CI, p = 0,004), 4.99 (95% CI, p = 0.000), and 3.15 (95% CI, p = 0.01), respectively. Haplotype TTTCTC, which is associated with MD, and haplotype GTCCTT, which was observed only in Yakut MD patients (never in MD patients of non-Yakut origin), were revealed. A low level of variability in the locus of DMRK gene in Yakuts (H(e) = 0.283) compared with other examined populations was noted. An analysis of pairwise genetic relationships between populations revealed their significant differentiation for all the examined loci. In addition, a low level of differentiation in territorial groups of Yakut populations (F(ST) = 0.79%), which was related to the high subdivision of the northern Eurasian population (F(ST) = 11.83%), was observed.

Phenotypic variability and molecular genetics in proximal myotonic myopathy.

INTRODUCTION: Myotonic dystrophy type 2 (DM2) is an autosomal dominant inherited disorder with (CCTG)n repeat expansion in intron 1 of the CNBP gene. METHODS: We studied the first 16 Greek DM2 patients who had undergone thorough evaluation. RESULTS: The age at diagnosis ranged from 38 to 69 years. The initial symptoms were proximal weakness, myalgias, and myotonia. Clinical myotonia was elicited in 10 patients, whereas electromyographic myotonic discharges were observed in almost all patients. Subcapsular cataract was frequently present, but cardiac arrhythmias were rare. CONCLUSIONS: In this study of Greek DM2 patients, proximal weakness was the most common initial symptom. Myalgias were also reported in a few patients, yet myotonia was not a major complaint. Although DM2 is considered relatively benign, there are patients who may be affected severely. Thus, a high index of suspicion must be maintained to make a timely diagnosis, especially in those of reproductive age.

Myotonic dystrophy.

Myotonic dystrophy (dystrophia myotonica, DM) is one of the most common lethal monogenic disorders in populations of European descent. DM type 1 was first described over a century ago. More recently, a second form of the disease, DM type 2 was recognized, which results from repeat expansion in a different gene. Both disorders have autosomal dominant inheritance and multisystem features, including myotonic myopathy, cataract, and cardiac conduction disease. This article reviews the clinical presentation and pathophysiology of DM and discusses current management and future potential for developing targeted therapies.

Distribution of CTG repeats at the DMPK gene in myotonic dystrophy patients and healthy individuals from the Mexican population.

Myotonic dystrophy type 1 (DM1), the most common form of adult muscular dystrophy, is caused by anormal expansion of CTG trinucleotide repeats located in the 3'-untranslated region of the DMPK gene. The clinical features of DM1 are multisystemic and highly variable, and the unstable nature of CTG expansion causes wide genotypic and phenotypic presentations. In this study, we described to our knowledge for the first time the molecular diagnosis of myotonic dystrophy type 1 patients in the Mexican population, applying a fluorescent PCR method in combination with capillary electrophoresis analysis of the amplified products. We identified expanded alleles in 45 out of 50 patients (90%) with clinical features of myotonic disease. Furthermore, genotyping of 400 healthy subjects revealed the presence of 25 different alleles, ranging in size from 5 to 34 repeats. The most frequent allele was 13 CTG repeats (38.87%) and the frequency for alleles over 18 CTG repeats was 6.7%. Molecular test is essential for DM1 diagnosis and distribution of the CTG repeat alleles present in the Mexican population are significantly different from those of other populations.

CTG repeats at the myotonic protein kinase gene in a healthy Chilean population sample.

OBJECTIVES: To study the variability at the myotonic dystrophy protein kinase (DMPK) gene in a Chilean sample of healthy people. DM1 is an autosomal dominant disorder caused by an expansion of a (CTG) repeat at the 3'-UTR of the gene DMPK. Healthy individuals have alleles under 35 repeats and diseased individuals have over 50. METHODS: Genotyping the number of (CTG) repeats at this gene in a sample of healthy Chilean people. RESULTS: Allele frequencies were significantly different from those of other populations. The most frequent allele was with five repeats. The frequency of larger alleles (>18 CTG repeats) was 11%, close to the European frequency (12%) and higher than the Japanese (8%) and Aboriginal Pehuenche samples (8%). CONCLUSIONS: Allelic frequencies in the Chilean sample studied were intermediate between those of the two ancestral populations (European and Pehuenche).

Prevalence of myotonic dystrophy in Israeli Jewish communities: inter-community variation and founder premutations.

In a comprehensive epidemiological survey among Jews living in Israel, the average prevalence of myotonic dystrophy (DM) was 15.7/10(5) (1 case in 6369) with intercommunity variations; the Ashkenazi Jews had the lowest rate, 5.7/10(5) (1 case in 17544) as compared to the rate in the Sephardim/Oriental Jews 20/10(5) (1 case in 5000) and the in the Yemenite Jews 47.3/10(5) (1 case in 2114). The rate of unrelated DM-sibships per 10(6) people of each community was used as an estimate of the transition rate from stable to unstable DMPK-(CTG)(n) alleles assuming that each transition is a beginning of a new DM sibship. This study indicated that the difference in the incidence of DM is a result of higher mutation rate in the non-Ashkenazi Jews (>50/10(6)) as compared to the rate in the Ashkenazi Jews (16.3/10(6)). The intragenic haplotype of the DM alleles was the same as that of the DM in many populations all over the world. However, two DM closely linked markers D19S207 and D19S112 were in linkage disequilibrium with the DM mutation in patients of Yemenite and Moroccan (the largest subgroup in the Sephardim Jews) extractions and not in the Ashkenazi patients. This observation indicated a common ancestral origin for the DM premutation in patients of the same ethnic origin. We concluded that the difference in the prevalence of DM among the Jewish communities is a consequence of founder premutations in the non-Ashkenazi Jewish communities.

[Analysis of expansion of the triplet repeat (CTG)n in myotonic dystrophy patients from Bashkir]. / Analiz ékspansii tripletnogo povtora (CTG)n u bol'nykh miotonicheskoi distrofiei iz Bashkiri.

A method was elaborated for simple and rapid diagnosis of myotonic dystrophy (MD). The method consists in estimating expansion of the CTG repeat in the myotonin protein kinase gene by means of PCR amplification of a gene fragment from genomic DNA and Southern hybridization of the amplified fragments with probe (CTG)9. Bashkir patients with Rossolimo-Steinert-Batten-Kurshmann MD were examined with this method.

Characteristics of myotonic dystrophy in Istria: molecular genetic approach. Part II: Analysis of genetic polymorphisms.

One of the world highest prevalence estimates of myotonic dystrophy (DM) has been reported in the Croatian region Istria. To analyse the population genetic characteristics of DM locus in Istria, two intragenic and three extragenic polymorphic markers were tested. The Southern blot technique was used for D19S63 locus analysis, whereas PCR analysis was performed for CKMM, Alu polymorphism, DMPK (G/T) intron 9/HinfI polymorphism, and D19S207 genetic markers. The compound haplotypes segregating with DM were established. A complete association between the DM mutation and D19S63, D19S207, intron 9/HinfI polymorphism and Alu polymorphism markers were found. In all DM chromosomes: D19S63 and Alu markers had the allele 1 in common; D19S207 had the allele 3 in common, DMPK (G/T) intron 9/HinfI marker had the allele 2 in common. The analysis of CKMM polymorphism revealed genotype heterogeneity; in DM chromosomes either allele 2 or allele 4 were found. The haplotype analysis in the population of Croatian Istria supports the linkage disequilibrium between the DM mutation and Alu polymorphism, intron 9/HinfI polymorphism, D19S63 and D19S207 markers as reported worldwide. The results of the haplotype analysis suggest a common origin of the mutation in Istrian population.

CTG repeats distribution and Alu insertion polymorphism at myotonic dystrophy (DM) gene in Amhara and Oromo populations of Ethiopia.

Myotonic dystrophy (DM) is a dominantly inherited neuromuscular disease, highly variable and multisystemic, which is caused by the expansion of a CTG repeat located in the 3' untranslated region of the DMPK gene. Normal alleles show a copy number of 5-37 repeats on normal chromosomes, amplified to 50-3000 copies on DM chromosomes. The trinucleotide repeat shows a trimodal allele distribution in the majority of the examined population. The first class includes alleles carrying (CTG)5, the second class, alleles in the range 7-18 repeats, and the third class, alleles (CTG) > or =19. The frequency of this third class is directly related to the prevalence of DM in different populations, suggesting that normal large-sized alleles predispose toward DM. We studied CTG repeat allele distribution and Alu insertion and/or deletion polymorphism at the myotonic dystrophy locus in two major Ethiopian populations, the Amhara and Oromo. CTG allele distribution and haplotype analysis on a total of 224 normal chromosomes showed significant differences between the two ethnic groups. These differences have a bearing on the out-of-Africa hypothesis for the origin of the DM mutation. In addition, (CTG) > or =19 were exclusively detected in the Amhara population, confirming the predisposing role of these alleles compared with the DM expansion-mutation.

Correlation between the incidence of myotonic dystrophy in different groups in Israel and the number of CTG trinucleotide repeats in the myotonin gene.

Myotonic dystrophy (DM) is associated with an increased number of CTG repeats in the 3' untranslated region of the myotonin gene. Because DM has been observed less frequently in Ashkenazic Jews and non-Jews than in North African and Yemenite Jews in Israel, a study of the CTG repeat polymorphism was undertaken in these four groups. Alleles from 126 unrelated healthy North African Jews, 103 Yemenite Jews, 103 Ashkenazic Jews, and 106 Israeli Moslem Arabs were studied by PCR analysis of the trinucleotide repeat in the DM gene, and the size distribution of the CTG repeat was determined. The alleles ranged in length from 5-28 repeats in the Yemenite Jews, 5-26 in Muslim Arabs and North African Jews, and 5-23 in the Ashkenazic Jews. North African and Yemenite Jews were found to have significantly more large repeats in the normal range than Ashkenazic Jews and Muslim Arabs (for over 18 repeats: 9.1% and 13%, respectively, compared to 2.4% and 3.3%, respectively; P < 0.0001). It is suggested that the more frequent occurrence of large CTG repeats in the normal range may represent a greater predisposition to DM.

The lower incidence of myotonic dystrophy in Ashkenazic Jews compared to North African Jews is associated with a significantly lower number of CTG trinucleotide repeats.

Myotonic dystrophy (DM) is associated with an increased number of CTG repeats in the 3' untranslated region of the myotonin gene. Because DM has been observed more frequently in North African Jews than in Ashkenazic Jews in Israel, a study of the CTG repeat polymorphism was undertaken in these 2 groups. Alleles from 70 unrelated North African subjects and 70 unrelated Ashkenazic subjects were studied by PCR analysis of the trinucleotide repeat in the DM gene to determine the ethnic distribution of the number of CTG repeats. The alleles ranged in length from 5 to 26 repeats in the North Africans and 5 to 23 in the Ashkenazim. As has been seen in other populations, none of the chromosomes had a 9-repeat length. North African Jews were found to have significantly more repeats in the normal range than Ashkenazim (for over 14 repeats: 34/140 compared to 7/140; p < 0.0001). It is suggested that this more frequent occurrence of a large number of CTG repeats in the normal range may represent a greater predisposition to DM.

Founder effect and prevalence of myotonic dystrophy in South Africans: molecular studies.

A high prevalence of myotonic dystrophy (DM) has been described in South African Caucasoid Afrikaans-speaking families in the northern Transvaal. Evidence is presented for a strong founder effect, with a single haplotype occurring on 68% of all Caucasoid DM chromosomes; among the Afrikaans speakers, the proportion was 83%. In addition to this major haplotype, five minor DM haplotypes in the Caucasoids and two minor haplotypes in DM individuals of mixed ancestry were found. All DM chromosomes, however, had a common haplotype core, namely, Alu (ins), HinfI-2 (intron 9), and TaqI-2 (D19S463). We have detected significant linkage disequilibrium between the DM mutation and particular alleles of the extragenic markers D19S112 and D19S207. Significant differences were found in allele and haplotype distributions in the Caucasoid DM and non-DM chromosomes and Negroid non-DM chromosomes. These findings together with the strong association of allele 3 at the D19S63 locus on 93% (14/15) of the South African DM chromosomes suggest that the majority of present-day DM mutations in South African Caucasoids may have originated from a common initial founder who introduced one of the European ancestral mutations.

Ethnicity and myotonic dystrophy: a possible explanation for its absence in sub-Saharan Africa.

The CTG trinucleotide repeat, in the myotonic dystrophy (DM) myotonin protein kinase gene, was studied by PCR analysis in a total of 246 unrelated South African Bantu-speaking Negroids, 116 San and 27 Pygmies. The size and distribution of the CTG repeat were determined and showed that the alleles ranged in length from 5 to 22 repeats. The most common CTG repeat is 5 (25% of chromosomes) in the South African Negroids but 11 (27% of chromosomes) in the San population and 12 (22% of chromosomes) in the Pygmies. The southern African Bantu-speaking Negroids and San were found to have significantly fewer large repeat length alleles than do Caucasoid and Japanese populations. Since DM has not been observed in southern African Negroids, it is possible that the occurrence of fewer large CTG repeats in the normal range may, in part, explain this absence. It seems likely, that the rare DM mutation event postulated to have occurred on a specific chromosomal haplotype, occurred after the migration of humans from Africa.

Myotonic dystrophy: genetic, clinical, and molecular analysis of patients from 41 Brazilian families.

Results of genealogical, DNA, and clinical findings in 41 families with 235 patients affected with myotonic dystrophy (DM) led to the following observations. (1) The relative proportion of affected patients among blacks is apparently lower than among whites or orientals. (2) A significant excess of males was observed. (3) The frequency of DM patients who did not reproduce was similar for males and females; however, female patients had on average 25% fewer children than male patients. (4) There was a significant intergenerational increase in the mean length of the CTG repeat which was also correlated with the severity of the phenotype. (5) No significant difference was observed in the mean size of the CTG repeat in offspring of male as compared to female transmitters. (6) With the exception of the congenital cases of maternal origin, the largest expansions were paternally inherited, but did not lead to congenital DM.

Absence of myotonic dystrophy in southern African Negroids is associated with a significantly lower number of CTG trinucleotide repeats.

Myotonic dystrophy (DM) is associated with an increased number of CTG repeats in the 3' untranslated region of the myotonin gene. Because DM has not been observed in southern African Negroids, a study of the CTG repeat polymorphism in this population was undertake. A total of 210 unrelated subjects was studied by PCR analysis of the trinucleotide repeat in the DM gene and the size and distribution of the CTG repeat were determined. The alleles ranged in length from five to 22 repeats. A previously undescribed BglI polymorphism was found which could lead to erroneous diagnosis of DM in people from this population. South African Negroids were found to have significantly fewer large repeat lengths than do white and Japanese populations. It is suggested that the occurrence of fewer large CTG repeats in the normal range may, in part, explain the absence of DM in southern African Negroids.