Deficiency of alpha-actinin-3 (ACTN3) occurs in different forms of muscular dystrophy.

The alpha-actinins belong to a superfamily of cytoskeletal proteins, and their role in human genetic diseases is still unclear. Therefore, they could be good candidates for muscular dystrophies of unknown etiology. We have analyzed alpha-actinin-3 (ACTN3) in muscle biopsies from a total of 54 patients. A complete deficiency was found in 9 patients: 2/12 with classical merosin-positive congenital MD (CMD), 1/12 with Severe Childhood Autosomal Recessive MD (DLMD), but with a positive IF pattern for the proteins of the sarcoglycan complex: 3/14 with mild limb-girdie MD (1LGMD2A and 2 yet unclassified), 1/10 with sarcoglycanopathies (LGMD2C), and 2/6 with Xp21 Duchenne MD (DMD). Patients within the same family, and with the same disease (DMD, LGMD2A, LGMD2C), were discordant for ACTN3 deficiency. Additionally, no correlation was found with the degree of muscle degeneration, nor with the clinical course. One ACTN3-deficient CMD patient showed no mRNA expression for the muscle ACTN3 gene, but the other ACTN3-deficient patients with different forms of muscular dystrophy showed very low or no mRNA expression as well. These results show that the deficiency of ACTN3 is a secondary effect in these dystrophies.

Severe nonspecific X-linked mental retardation caused by a proximally Xp located gene: intragenic heterogeneity or a new form of X-linked mental retardation?

X-linked mental retardation (XLMR) can be subdivided into syndromic and nonsyndromic or nonspecific. Patients with non-syndromal XLMR show no characteristic manifestations, biochemical defects, or distinct fragile sites. Nevertheless, nonspecific XLMR seems to be heterogeneous. To determine the number and location of the genes responsible for XLMR, linkage studies in large pedigrees have to be performed. Here we report the data of linkage analysis in a large Brazilian family with 7 patients affected by a severe form of XLMR, with no other associated malformations. All the obligate carriers are normal. A close linkage without recombination (lod scores 1.95 and 3.25) was found between the disease locus and polymorphic DNA loci DXS255 (Xp11.22), DXS14 (Xp11.21). These results suggest that the gene responsible for the disease in this family maps in the Xp11-cent of the X chromosome. Positive lod scores in this region have also been reported for other XLMR genealogies, but with a much milder phenotype. The possibility of intragenic or locus heterogeneity is discussed.