Mutations in the DMD gene, encoding the dystrophin protein, are responsible for the dystrophinopathies Duchenne Muscular Dystrophy (DMD), Becker Muscular Dystrophy (BMD), and X-linked Dilated Cardiomyopathy (XLDC). Mutation analysis has traditionally been challenging, due to the large gene size (79 exons over 2.2 Mb of genomic DNA). We report a very large aggregate data set comprised of DMD mutations detected in samples from patients enrolled in the United Dystrophinopathy Project, a multicenter research consortium, and in referral samples submitted for mutation analysis with a diagnosis of dystrophinopathy. We report 1111 mutations in the DMD gene, including 891 mutations with associated phenotypes. These results encompass 506 point mutations (including 294 nonsense mutations) and significantly expand the number of mutations associated with the dystrophinopathies, highlighting the utility of modern diagnostic techniques. Our data supports the uniform hypermutability of CGA>TGA mutations, establishes the frequency of polymorphic muscle (Dp427m) protein isoforms and reveals unique genomic haplotypes associated with `private' mutations. We note that 60% of these patients would be predicted to benefit from skipping of a single DMD exon using antisense oligonucleotide therapy, and 62% would be predicted to benefit from an inclusive multi-exon skipping approach directed toward exons 45 through 55.

A prospective study of 114 patients with DMD provided data for "power" calculations for future therapeutic trials. There was a decline in strength of 0.4 units per year (on a 0-10 scale). Contractures of the iliotibial bands, hip flexors, and heel cords developed before 6 years. Contractures of other joints accompanied the increased use of wheelchairs. All children walked until 8 years with functional "improvement" between 3-6 years. Children of the same age varied widely in their strength, degree of contracture, and functional abilities. Fifteen percent of the patients appear to have a milder variety of the disease and are termed "outliers." To test a drug which might slow the disease to 25% of its original rate of progression, two groups (placebo and treatment) of 40 patients each would have to be followed for one year.

We have determined the value of creatine and pyruvate kinase (CK and PK) in carrier detection by evaluating 811 females in 73 families participating in the Collaborative Investigation of Duchenne Dystrophy. Thirty-nine obligate carriers, 244 normal controls (paternal females), as well as 76 possible carriers and 351 carrier suspects had three CK and PK specimens analyzed at a central laboratory. The CK and PK values varied with age in normals: both fell with age early in life, and CK rose after the fifth decade. Discriminant analysis indicated that the combination of mean CK and PK corrected for age yielded the best data for calculation of carrier probability. Using the best model, only 45% of obligate carriers could be identified at a false-positive rate of 2.5%. Daughters of obligate carriers have a disproportionate decline in CK and PK with age as compared to noncarrier females, suggesting that the rate of carrier detection will be higher in the first two decades. Our low rate of carrier detection, as compared to other studies, may reflect both the age of our obligate carrier population and the use of a control group that is more representative of the carrier population.

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Sex-specific genetic data favor a specific variant of the oral history of the kingdom of Nso' (a Grassfields city-state in Cameroon) in which the royal family traces its descent from a founding ancestress who married into an autochthonous hunter-gatherer group. The distributions of Y chromosome and mitochondrial DNA variation in the Nso' in general and in the ruling dynasty in particular are consistent with specific Nso' marriage practices, suggesting strict conservation of the royal social class along agnatic lines. This study demonstrates the efficacy of using genetics to augment other sources of information (e.g., oral histories, archaeology, and linguistics) when seeking to recover the histories of African peoples.