Possible influences on the expression of X chromosome-linked dystrophin abnormalities by heterozygosity for autosomal recessive Fukuyama congenital muscular dystrophy.

Abstract

Abnormalities of dystrophin, a cytoskeletal protein of muscle and nerve, are generally considered specific for Duchenne and Becker muscular dystrophy. However, several patients have recently been identified with dystrophin deficiency who, before dystrophin testing, were considered to have Fukuyama congenital muscular dystrophy (FCMD) on the basis of clinical findings. Epidemiologic data suggest that only 1/3500 males with autosomal recessive FCMD should have abnormal dystrophin. To explain the observation of 3/23 FCMD males with abnormal dystrophin, we propose that dystrophin and the FCMD gene product interact and that the earlier onset and greater severity of these patients' phenotype (relative to Duchenne muscular dystrophy) are due to their being heterozygous for the FCMD mutation in addition to being henizygous for Duchenne muscular dystrophy, a genotype that is predicted to occur in 1/175,000 Japanese males. This model may help explain the genetic basis for some of the clinical and pathological variability seen among patients with FCMD, and it has potential implications for understanding the inheritance of other autosomal recessive disorders in general. For example, sex ratios for rare autosomal recessive disorders caused by mutations in proteins that interact with X chromosome-linked gene products may display predictable deviation from 1:1.

The molecular basis of genetic dominance.

“…Examples include the interaction of a and 3 tubulin mutations in Drosophila'06 and, more speculatively, the enhanced severity of dystrophin mutations in trans to an abnormal allele for autosomal recessive Fukuyama congenital muscular dystrophy. 107 An allied phenomenon, called negative complementation or metabolic interference, occurs when two alleles at the same locus interact to give a more severe phenotype in the compound heterozygote than in either homozygote. For example, Abruptex (Abx) mutations of the Drosophila Notch gene fall into two genetic types, "enhancers" and "suppressors" of Notch.…”

Duchenne Muscular Dystrophy and Early Onset Hypertrophic Cardiomyopathy associated with Mutations in Dystrophin and Hypertrophic Cardiomyopathy-Associated Genes

“…The deletion of exons 51–54 of dystrophin is predicted to cause an out of frame splicing of exon 50 to exon 55, resulting in the absence of the dystrophin protein which should cause a severe form of DMD as reported. 12 DC was observed in patients with gross deletions of the dystrophin gene mainly deletions of exons 48–49. 3 13 14 Deletions in exons 48, 45 to 53, and 49 have also been reported to cooccur with cardiomyopathy in some of the cases; 15 16 but the connection between the cardiac phenotype to the dystrophin genetic composition was not established.…”

From genotype to phenotype: genetics and medical practice in the new millennium

“…To explain the high frequency of dystrophin de¢ciency in males with Fukuyama muscular dystrophy, it has been suggested that the Fukuyama muscular Table 3. Some mechanisms for the phenotypic diversity of thalassaemia heterogeneity of mutations at the b-globin gene locus action of modi¢ers primary: a-globin genes; g-globin genes secondary: multiple loci, involving bone, iron and bilirubin metabolism; others variability due to co-selection acquired factors environment geographical, social, cultural dystrophy gene product normally interacts with dystrophin, and that the phenotype in these severely a¡ected males re£ects heterozygosity for the Fukuyama mutation coupled with a DMD gene mutation (Beggs et al 1992). Retinitis pigmentosa is the name given to a set of inherited degenerations of the retina.…”