More than a billion humans worldwide are predicted to be completely deficient in the fast skeletal muscle fiber protein alpha-actinin-3 owing to homozygosity for a premature stop codon polymorphism, R577X, in the ACTN3 gene. The R577X polymorphism is associated with elite athlete status and human muscle performance, suggesting that alpha-actinin-3 deficiency influences the function of fast muscle fibers. Here we show that loss of alpha-actinin-3 expression in a knockout mouse model results in a shift in muscle metabolism toward the more efficient aerobic pathway and an increase in intrinsic endurance performance. In addition, we demonstrate that the genomic region surrounding the 577X null allele shows low levels of genetic variation and recombination in individuals of European and East Asian descent, consistent with strong, recent positive selection. We propose that the 577X allele has been positively selected in some human populations owing to its effect on skeletal muscle metabolism.

Purpose By incorporating major developments in genetics, ophthalmology, dermatology, and neuroimaging, to revise the diagnostic criteria for neurofibromatosis type 1 (NF1) and to establish diagnostic criteria for Legius syndrome (LGSS). Methods We used a multistep process, beginning with a Delphi method involving global experts and subsequently involving non-NF experts, patients, and foundations/patient advocacy groups. Results We reached consensus on the minimal clinical and genetic criteria for diagnosing and differentiating NF1 and LGSS, which have phenotypic overlap in young patients with pigmentary findings. Criteria for the mosaic forms of these conditions are also recommended. Conclusion The revised criteria for NF1 incorporate new clinical features and genetic testing, whereas the criteria for LGSS were created to differentiate the two conditions. It is likely that continued refinement of these new criteria will be necessary as investigators (1) study the diagnostic properties of the revised criteria, (2) reconsider criteria not included in this process, and (3) identify new clinical and other features of these conditions. For this reason, we propose an initiative to update periodically the diagnostic criteria for NF1 and LGSS.

A common polymorphism (R577X) in the ACTN3 gene results in complete deficiency of ␣-actinin-3 protein in ϳ16% of humans worldwide. The presence of ␣-actinin-3 protein is associated with improved sprint/power performance in athletes and the general population. Despite this, there is evidence that the null genotype XX has been acted on by recent positive selection, likely due to its emerging role in the regulation of muscle metabolism. ␣-Actinin-3 deficiency reduces the activity of glycogen phosphorylase and results in a fundamental shift toward more oxidative pathways of energy utilization. Deficiency of the fast-fiber skeletal muscle protein ␣-actinin-3 is common in the general population due to a polymorphic-null allele in the ACTN3 gene. Numerous independent studies have established that the absence of ␣-actinin-3 is detrimental to sprint and power performance in athletes and in the general population (1,25,55,63,66). The sarcomeric ␣-actinins have long been considered to be primarily structural proteins. However, recent data suggest that ␣-actinin-3 plays a significant role in the regulation of muscle metabolism. ␣-Actinin-3 deficiency results in a shift in the characteristics of fast glycolytic muscle fibers toward those of slow muscle fibers with oxidative metabolism (48,49,62). This review examines the emerging role of ␣-actinin-3 in regulation of skeletal muscle metabolism. The ␣-Actinin Family of ProteinsThe ␣-actinins are a family of actin-binding proteins that have been identified in a diverse range of organisms, suggesting an ancient origin (3,8,33,50). The ␣-actinin protein structure is comprised of three domains; an NH 2 -terminal actin-binding domain, a central rod domain containing four internal repeated 122-amino acid motifs, and a COOH-terminal region containing two EF-hand calcium binding motifs. The four repetitive motifs found in ␣-actinin share homology with spectrin, suggesting a common evolutionary origin of the ␣-actinin proteins and the spectrin family of actin binding cytoskeletal proteins, of which dystrophin is a member (13, 75). There is marked evolutionary conservation of the ␣-actinin genes across species, particularly within the NH 2 -terminal actin-binding domain (9). There are four ␣-actinin genes in humans, ACTN1-ACTN4 (9, 85). ACTN1 and ACTN4 contain functional calcium-sensitive EF hands, whereas the skeletal muscle or sarcomeric ␣-actinins, encoded by ACTN2 and ACTN3, have EF hands that are not calcium sensitive (15). In humans, ␣-actinin-2 is expressed in the heart, in all skeletal muscle fibers, and in the brain, whereas ␣-actinin-3 is expressed only in fast glycolytic skeletal muscle fibers, is not present in cardiac muscle, and has low levels of expression in the brain (50). These two proteins diverged from one another following a gene duplication event over 300 million years ago (mya), but have retained considerable sequence similarity (43). Human ␣-actinin-2 and ␣-actinin-3 are 79% identical and 91% similar at the amino acid level (9, 42).The sarcomeres are repeating un...