Inheritance. DMD has an incidence of ~1 in 3300 live male births, with a calculated mutation rate of 10⁻⁴, an order of magnitude higher than the rate observed in genes involved in most other genetic diseases. In fact, given a production of ~8 × 10⁷ sperm per day, a normal male produces a sperm with a new mutation in the DMD gene every 10 to 11 seconds! In Chapter 7, DMD was presented as a typical X-linked recessive dis order that is lethal in males, so that one-third of cases are predicted to be due to new mutations and two-thirds of patients have carrier mothers. The great majority of carrier females have no clinical mani festations, although ~70% have slightly elevated levels of serum creatine kinase. In accordance with random inactivation of the X chromosome, however, the X chromosome carrying the normal DMD allele appears to be inactivated above a critical threshold of cells in some female heterozygotes. Nearly 20% of adult female carriers have some muscle weakness; whereas in 8%, life-threatening cardiomyopathy and serious proximal muscle disability occur. In rare instances, females have been described with DMD. Some have X;autosome translocations, whereas others have only one X chromosome (Turner syndrome) with a DMD pathogenic variant on that chromosome.

BMD accounts for ~15% of the variants at the locus. An important genetic distinction between these allelic phenotypes is that whereas DMD is a genetic lethal, the reproductive fitness of males with BMD is high (up to ~70% of normal) so that they can transmit the mutant gene to their daughters. Consequently, and in contrast to DMD, a high proportion of BMD cases are inherited, and relatively few (only ~10%) represent new mutations.

The DMD Gene and Its Product. The most remark able feature of the DMD gene is its size, estimated to be >2000kb, or ~1.5% of the entire X chromosome. This huge gene is among the largest known in any species, by an order of magnitude. The high mutation rate can be at least partly explained by the fact that the locus is a large target for mutation but, as described later, it is also structurally prone to deletion and duplication. The DMD gene is complex, with 79 exons and seven tissue-specific promoters. In muscle, the large (14-kb) dystrophin transcript encodes a huge 427-kD protein. In accordance with the clinical phenotype, the protein is most abundant in skeletal and cardiac muscle, although many tissues express at least one dystrophin isoform.

The Molecular and Physiologic Defects in Becker Muscular Dystrophy and Duchenne Muscular Dystrophy. The most common molecular defects in patients with DMD are deletions (60% of alleles), which are not randomly distributed. Rather, they are clustered in either the 5′ half of the gene or in a central region that encompasses an apparent deletion hot spot. The mechanism of deletion in the central region is unknown, but it appears to involve the tertiary structure of the genome and, in some cases, recombination between Alu repeat sequences in large central introns. Point variants account for approximately one-third of the alleles and are randomly distributed throughout the gene.

The absence of dystrophin in DMD destabilizes the myofiber membrane, increasing its fragility and allowing increased Ca++ entry into the cell, with subsequent activation of inflammatory and degenerative pathways.

In addition, the chronic degeneration of myofibers eventually exhausts the pool of myogenic stem cells that are normally activated to regenerate muscle. This reduced regenerative capacity eventually leads to the replacement of muscle with fat and fibrotic tissue.

The Dystrophin Glycoprotein Complex. Dystrophin is a structural protein that anchors the DGC at the cell membrane. The DGC is a veritable constellation of poly peptides associated with more than a dozen genetically distinct muscular dystrophies (Fig. 1). This complex serves several major functions. First, it is thought to be essential for the maintenance of muscle membrane integrity, by linking the actin cytoskeleton to the extracellular matrix. Second, it is required to position the proteins in the complex at the sarcolemma. Although the function of many of the proteins in the complex is unknown, their association with diseases of muscle indicates that they are essential components of the complex. Pathogenic variants in several of these proteins cause autosomal recessive limb girdle muscular dystrophies and other congenital muscular dystrophies (see Fig. 1).

Fig1. In muscle, dystrophin links the extracellular matrix (laminin) to the actin cytoskeleton. Dystrophin interacts with a multimeric complex composed of the dystroglycans (DG), the sarcoglycans, the syntrophins, and dystrobrevin. The α,β-dystroglycan complex is a receptor for laminin and agrin in the extracellular matrix; pathogenic variants in 14 glycosyltransferase genes affecting the complex cause various forms of muscular dystrophy with or without brain and eye involvement (MDDGs, muscular dystrophy dystroglycanopathies). The function of the sarcoglycan complex is uncertain, but it is integral to muscle function; pathogenic variants in the sarcoglycans have been identified in limb girdle muscular dystrophies (LGMD). Pathogenic variants in laminin type 2 (merosin) cause a congenital muscular dystrophy (CMD). The branched structures represent glycans. The WW domain of dystrophin is a tryptophan-rich, protein-binding motif. BMD, Becker muscular dystrophy; DMD, Duchenne muscular dystrophy; Syn, Syntrophins; XDCM, X-linked dilated cardiomyopathy. (Courtesy R. Cohn, The Hospital for Sick Children, Toronto.)

That each component of the DGC is affected by variants that cause other types of muscular dystrophies highlights the principle that no protein functions in isolation but rather is a component of a biologic pathway or a multiprotein complex. Variants in the genes encoding other components of a pathway or a complex often lead to genocopies.

Posttranslational Modification of the Dystrophin Glycoprotein Complex. Five of the muscular dystrophies associated with the DGC result from pathogenic variants in glycosyltransferases, leading to hypoglycosylation of α-dystroglycan. That five proteins are required for the posttranslational modification of one other poly peptide testifies to the critical nature of glycosylation to the function of α-dystroglycan in particular but, more generally, to the importance of posttranslational modifications for the normal function of most proteins.

اخر الاخبار

اخبار العتبة العباسية المقدسة

شعبة مدارس الكفيل تنظم ورشة عن التمكين الإرشادي ومهارات التعامل مع الأطفال واليافعين

العتبة العباسية المقدسة تستقبل وفود المؤتمر العلمي الدولي للسيد المجاهد (قدس سره)

قسم شؤون المعارف يقيم ندوة تعريفية عن مؤتمر التراث البصري في جامعة بابل

شعبة التوجيه الديني النسوي تقيم مجلس عزاء بذكرى وفاة السيدة زينب (عليها السلام)

المزيد

الآخبار الصحية

طبيب يكشف أفضل مكمل غذائي لتحسين المزاج ودعم الصحة النفسية

دراسة جديدة تكشف أضرار الأطعمة الجاهزة على القلب ؟

6 أطعمة طبيعية تهدئ الزكام دون أدوية.. تعرف عليهم

ماذا يحدث لأعراض الزكام عند تناول الثوم بانتظام؟

المزيد

الآخبار التكنلوجية

ابتكار ثوري في بطاريات السيارات الكهربائية.. سعة أعلى 4 مرات

ماذا يحدث لجسمك عند شرب الماء الساخن يوميا؟

7 فوائد "خفية" لشرب شاي الكركديه كل يوم

دراسة تكشف قدرة الحيتان على سماع الأصوات منخفضة وعالية التردد من مسافة بعيدة

المزيد

مواضيع ذات صلة

Prenatal Diagnosis of Hereditary Genetic Diseases

Prenatal Diagnosis of Non-hereditary Genetic Diseases

Clinical Applications of Gene Testing in Muscular Dystrophy

Pathogenic Variants of an Enzyme Inhibitor: α1-Antitrypsin Deficiency

Lysosomal Storage Diseases: A Unique Class of Enzymopathies

Aminoacidopathies

Diseases due to pathogenic variants in different classes of proteins

Renal cysts and diabetes (HNF1B MODY)

Maternally inherited diabetes and deafness

Genetic testing in neonatal diabetes

Human Hemoglobin and Associated Diseases

The Relationship Between Genotype and Phenotype in Genetic Disease