Intrafamilial variability in dystrophin abundance correlated with difference in the severity of the phenotype

doi:10.1016/0022-510X(93)90189-6

Journal of the Neurological Sciences

Volume 119, Issue 1, October 1993, Pages 38-42

https://doi.org/10.1016/0022-510X(93)90189-6 Get rights and content

Abstract

In Duchenne muscular dystrophy, the progression of the disease is always severe and predictable, while in Becker dystrophy there is a wide variability (intra and inter familial) in the severity of the phenotype. We report here a family in which the proband, who is currently 15 years old, is showing a severe DMD progression, while his affected maternal uncle, aged 29, has a more benign course, compatible with BMD. No DNA deletion was detected in both patients. Dystrophin analysis through immunofluorescence and western blotting showed a negative pattern in the youngest patient and a positive one in the oldest. Apparently, this is the first report on intrafamilial variability in dystrophin abundance correlated with a difference in the severity of the phenotype.

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Cited by (16)

Milder course in Duchenne patients with nonsense mutations and no muscle dystrophin
2014, Neuromuscular Disorders
Citation Excerpt :
A family with clinically discordant relatives have been previously reported by us in a maternal uncle and his nephew. But, differently from the present cases proteins and molecular analyses revealed that the uncle with a milder course had some muscle dystrophin as a result of an alternative splicing in the dystrophin gene [6,7]. Kesari et al. [8] reported a high rate of exceptions in the reading-frame rule in a study of 75 patients, mainly in BMD patients involving the N-terminal region of the gene.
Duchenne muscular dystrophy (DMD), a severe and lethal condition, is caused by the absence of muscle dystrophin. Therapeutic trials aiming at the amelioration of muscle function have been targeting the production of muscle dystrophin in affected Duchenne patients. However, how much dystrophin is required to rescue the DMD phenotype remains an open question. We have previously identified two exceptional golden retriever muscular dystrophy (GRMD) dogs with a milder course despite the total absence of muscle dystrophin. Here we report two unusual patients carrying nonsense mutations in the DMD gene and dystrophin deficiency but with an unexpectedly mild phenotype. Three reported polymorphisms, respectively in genes LTBP4, SPP1 and ACTN3 were excluded as possible DMD genetic modifiers in our patients. Finding the mechanisms that protect some rare patients and dogs from the deleterious effect of absent muscle dystrophin is of utmost importance and may lead to new avenues for treatment. Importantly, these observations indicate that it is possible to have a functional large muscle even without dystrophin.
Family study allows more optimistic prognosis and genetic counselling in a child with a deletion of exons 50-51 of the dystrophin gene
2007, Archives de Pediatrie
Les délétions en phase du gène de la dystrophine, impliquant des exons codant pour le domaine central de la protéine, sont associées à un phénotype très variable, et sont parfois même retrouvées chez des individus asymptomatiques. L'absence d'histoire familiale de dystrophie musculaire rend le conseil génétique difficile.
Un garçon de 4 ans a présenté des difficultés transitoires à la marche vers l'âge de 2 ans puis des épisodes de chutes à partir de l'âge de 3 ans. L'examen clinique ne montrait pas de faiblesse musculaire. La valeur des CPK était élevée (1300 UI). L'EMG était normal. L'étude histologique musculaire a montré une rhabdomyolyse sans signes évocateurs de dystrophie musculaire. Les immunomarquages pour la dystrophine, la mérosine et la dysferline étaient normaux. L'étude des protéines musculaires en western blot a montré une diminution du poids moléculaire des bandes correspondant à la dystrophine. L'étude par PCR multiplex du gène de la dystrophine a mis en évidence une délétion des exons 50 et 51, en phase. L'étude des marqueurs intragéniques et la PCR quantitative suggéraient que cette délétion était héritée de la mère. L'étude familiale a montré que son grand-père, âgé de 69 ans, ainsi que 3 autres hommes âgés de 28 à 55 ans étaient porteurs, bien qu'asymptomatiques et sans signe clinique. Les symptômes du patient ont totalement régressé. Son échographie cardiaque était normale. Sa tante maternelle, qui était enceinte, a poursuivi sa grossesse après avoir été informée des résultats de l'étude familiale.
Cette observation montre l'importance de l'étude familiale pour le pronostic et le conseil génétique chez un jeune garçon présentant un tableau clinique atypique ou une élévation isolée des enzymes musculaires, en l'absence d'antécédent familial de dystrophinopathie.
In frame deletions of exons encoding the central rod domain of dystrophin have been associated with a highly variable phenotype, including asymptomatic individuals. The lack of family history impairs accurate genetic counselling.
We report on a 4-year-old child suffering from transient episodes of limping at the age of 2 and several episodes of fall since the age of 3. Clinical examination did not show muscle weakness. CPK levels were increased (1300 UI). EMG was normal. Muscle histology showed a rhabdomyolysis without features of muscular dystrophy. Immunolabelling for dystrophin, merosin and dysferlin were normal. Western blot analysis of muscular proteins showed reduced-size dystrophin bands and a slightly reduced intensity for dystrophin, α and γ-sarcoglycan. Multiplex PCR of the dystrophin gene showed an in-frame deletion of exons 50-51, predicted to be associated to a Becker type of dystrophinopathy. Intragenic markers and quantitative PCR suggested maternal inheritance. This was confirmed by testing the maternal grand-parents, revealing that the asymptomatic 69-year-old grand father was a carrier. Three additional healthy males, whose ages ranged from 28 to 55 years and who were asymptomatic, also carried the mutation. The proband became spontaneously asymptomatic and cardiac echography was normal. In light of these data, genetic counselling was more reassuring and the mutation carrier maternal aunt, who was pregnant, decided to continue the pregnancy.
This case report emphasizes the importance of family molecular analysis, especially in males from the maternal lineage, for genetic counselling of dystrophinopathies associated to atypical features or to an isolate increase of muscular enzymes level in a young boy with no positive family history.
Genetic modifiers of muscular dystrophy: Implications for therapy
2007, Biochimica et Biophysica Acta - Molecular Basis of Disease
The genetic understanding of the muscular dystrophies has advanced considerably in the last two decades. Over 25 different individual genes are now known to produce muscular dystrophy, and many different “private” mutations have been described for each individual muscular dystrophy gene. For the more common forms of muscular dystrophy, phenotypic variability can be explained by precise mutations. However, for many genetic mutations, the presence of the identical mutation is associated with marked phenotypic range that affects muscle function as well as cardiac function. The explanation for phenotype variability in the muscular dystrophies is only now being explored. The availability of genetically engineered animal models has allowed the generation of single mutations on the background of highly inbred strain. Phenotypic variation that is altered by genetic background argues for the presence of genetic modifier loci that can ameliorate or enhance aspects of the dystrophic phenotype. A number of individual genes have been implicated as modifiers of muscular dystrophy by studies in genetically engineered mouse models of muscular dystrophy. The value of these genes and products is that the pathways identified through these experiments may be exploited for therapy.
Screening for antisense modulation of dystrophin pre-mRNA splicing
2002, Neuromuscular Disorders
Most gene therapy approaches to genetic disorders aim to compensate loss-of-function by introducing recombinant cDNA-based minigenes into diseased tissues. The current report represents an ongoing series of studies designed to correct genetic mutations at the post-transcriptional level. This strategy modifies the binding of components of the spliceosome by high affinity hybridisation of small complementary (antisense) RNA oligonucleotides to specific pre-mRNA sequences. These, so-called ‘splicomer’ reagents are chemically modified to impart bio-stability, and are designed to cause skipping of mutant frame-shifting exon sequences leading to restoration of the reading frame and an internally deleted but partially functional gene product. For instance, Duchenne muscular dystrophy is generally caused by frame-shift mutations in the dystrophin gene, whereas in-frame deletions of up to 50% of the central portion of the gene cause Becker muscular dystrophy, a much milder myopathy, which in some cases can remain asymptomatic to old age. In the mdx mouse model of Duchenne muscular dystrophy, a mutation in exon 23 of the dystrophin gene creates a stop codon and leads to a dystrophin-deficient myopathy in striated muscle. In previous studies, we have demonstrated that forced skipping of this mutant exon by treatment of mdx muscle cells with splicomer oligonucleotides can generate in-frame dystrophin transcripts and restore dystrophin expression. Here, we report the results of an optimisation of splicomer sequence design by the use of both high-throughput arrays and biological screens. This has resulted in specific and, importantly, exclusive skipping of the targeted exon in greater than 60% of dystrophin mRNA, leading to the de novo synthesis and localisation of dystrophin protein in cultured mdx muscle cells.
Elevation of serum creatine kinase as the only manifestation of an intragenic deletion of the dystrophin gene in three unrelated families
1998, European Journal of Paediatric Neurology
This study reports three children from three unrelated families, aged from 9 to 12 years, who were investigated because of the incidental finding of elevated serum creatine kinase (CK) levels and were found to have a dystrophinopathy. The molecular defect consisted of a deletion of variable extent within the central rod domain of the dystrophin gene, involving either exons 32–44 or 48–51 or 48–53. In each family we found the same deletion in at least one adult male relative aged from 40 to 77 years, who was either completely asymptomatic or had very mild muscle involvement (thin muscles and/or mild scoliosis), with normal or borderline CK levels. This study suggests once again that deletions of the central rod domain of dystrophin may be associated with elevation of serum CK as the only manifestation and that prediction of the clinical severity based solely on the molecular findings should be interpreted with caution.
4. Gene Therapy of Duchenne Muscular Dystrophy
1997, Advances in Genetics
This chapter reviews the gene therapy of Duchenne muscular dystrophy (DMD). DMD is an X-linked disorder affecting about 1:3500 live male births. It is a more complex disease involving the heart and the central nervous system (CNS), as well as peripheral nerves and smooth muscle; it is generally noticed between the ages of 2 and 5 years. Skeletal muscle is the tissue with the most striking pathology in patients lacking dystrophin, but heart and central nervous system (CNS) may also be affected. More recent studies using magnetic resonance spectroscopy indicate that DMD patients have significant higher values than controls in the brain ratios of inorganic phosphate to ATP to phosphomonoesters, and to phosphocreatine. Animal models are becoming increasingly important in testing potential therapeutic approaches for DMD. Histopathologic analysis of skeletal muscle appears to be the easiest and most reliable way of assessing the efficacy of dystrophin gene replacement, particularly if the analysis is carried out in the diaphragm.

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Research articleIntrafamilial variability in dystrophin abundance correlated with difference in the severity of the phenotype

Abstract

J. Neurol. Sci.

Cell

Neuron

Cell

Cell

Cell

Genomics

J. Neurol. Sci.

Lancet

J. Neurol. Sci.

J. Neurol. Sci.

J. Chron. Dis.

J. Neurol. Sci.

Immunostaining of skeletal and cardiac muscle surface membrane with antibody against Duchenne muscular dystrophy peptide

Nature

Molecular and clinical correlations of deletions leading to Duchenne and Becker muscular dystrophies

Neurology

Detection of 98% of DMD/BMD deletions by PCR

Hum. Genet.

Exploring the molecular basis for variability among patients with Becker muscular dystrophy: dystrophin gene and protein studies

Am. J. Hum. Genet.

Partial dystrophin deficiency in monozygous twin carriers of the Duchenne gene discordant for clinical myopathy

Neurology

Clinical investigation in Duchenne dystrophy. 2. Determination of the “power” of therapeutic trials based on the history natural

Muscle Nerve

Differentiation of Duchenne and Becker muscular dystrophy phenotypes with amino- and carboxy-terminal antisera specifiec for dystrophin

Am. J. Hum. Genet.

Research article
Intrafamilial variability in dystrophin abundance correlated with difference in the severity of the phenotype