Premutation allele pool in myotonic dystrophy type 2.

BACKGROUND: The myotonic dystrophies (DM1, DM2) are the most common adult muscle diseases and are characterized by multisystem involvement. DM1 has been described in diverse populations, whereas DM2 seems to occur primarily in European Caucasians. Both are caused by the expression of expanded microsatellite repeats. In DM1, there is a reservoir of premutation alleles; however, there have been no reported premutation alleles for DM2. The (CCTG)(DM2) expansion is part of a complex polymorphic repeat tract of the form (TG)(n)(TCTG)(n)(CCTG)(n)(NCTG)(n)(CCTG)(n). Expansions are as large as 40 kb, with the expanded (CCTG)(n) motif uninterrupted. Reported normal alleles have up to (CCTG)(26) with one or more interruptions. METHODS: To identify and characterize potential DM2 premutation alleles, we cloned and sequenced 43 alleles from 23 individuals. Uninterrupted alleles were identified, and their instability was confirmed by small-pool PCR. We determined the genotype of a nearby single nucleotide polymorphism (rs1871922) known to be in linkage disequilibrium with the DM2 mutation. RESULTS: We identified three classes of large non-DM2 repeat alleles: 1) up to (CCTG)(24) with two interruptions, 2) up to (CCTG)(32) with up to four interruptions, and 3) uninterrupted (CCTG)(22-33). Large non-DM2 alleles were more common in African Americans than in European Caucasians. Uninterrupted alleles were significantly more unstable than interrupted alleles (p = 10(-4) to 10(-7)). Genotypes at rs1871922 were consistent with the hypothesis that all large alleles occur on the same haplotype as the DM2 expansion. CONCLUSIONS: We conclude that unstable uninterrupted (CCTG)(22-33) alleles represent a premutation allele pool for DM2 full mutations.

MGEA5-14 polymorphism and type 2 diabetes in Mexico City.

A family-based study has recently reported that a variant located in intron 10 of the gene MGEA5 increases susceptibility to Type 2 Diabetes (T2D). We evaluated the distribution of this SNP in a sample of T2D patients (N = 271) and controls (N = 244) from Mexico City. The frequency of the T allele was higher in the cases (2.6%) than in the controls (1.8%). After adjusting for age, sex, BMI, education, and individual ancestry the odds ratio was 1.60 but the 95% confidence interval was wide and overlapped 1 (0.52-4.86, P-value : 0.404). In order to characterize the distribution of the MGEA5-14 polymorphism in the relevant parental populations, we genotyped this variant in European (and European Americans), West African, and Native American samples. The T-allele was present at a frequency of 2.3% in Spain, 4.2% in European Americans, and 13% in Western Africans, but was absent in two Native American samples from Mexico and Peru. Given the low frequency of the T-allele, further studies using large sample sizes will be required to confirm the role of this variant in T2D.

Trinucleotide repeat length variation in the human ribosomal protein L14 gene (RPL14): localization to 3p21.3 and loss of heterozygosity in lung and oral cancers.

Chromosome 3p is consistently deleted in lung cancer, oral squamous cell carcinoma, and renal cell carcinoma, and is believed to contain several tumor suppressor genes. We have shown a role for chromosome 3 in tumor suppression by microcell-mediated chromosome transfer experiments. We have isolated a gene that is located at 3p21.3 within the smallest region of deletion overlap in lung tumors and is the human homolog of the ribosomal protein L14 gene (RPL14). The RPL14 sequence contains a highly polymorphic trinucleotide repeat array which encodes a variable-length polyalanine tract. Genotype analysis of RPL14 shows that this locus is 68% heterozygous in the normal population, compared with 25% in non-small cell lung cancer (NSCLC) cell lines (p = 0.008). Cell cultures derived from normal bronchial epithelium show a 65% level of heterozygosity, reflecting that of the normal population. Squamous cell carcinoma of the head and neck (SCCHN), which has the same risk factors as lung cancer and is hypothesized to have a similar etiology, demonstrates 54% loss of heterozygosity at the RNA level, suggesting that transcriptional loss may be a primary mechanism of RPL14 alteration in SCCHN. In addition, RPL14 shows significant differences in allele frequency distribution in ethnically-defined populations, making this sequence a useful marker for the study of ethnicity-adjusted lung cancer risk.