Dominantly inherited muscle disorders: understanding their complexity and exploring therapeutic approaches

Abstract

Treatments for disabling and life-threatening hereditary muscle disorders are finally close to becoming a reality. Research has thus far focused primarily on recessive forms of muscle disease. The gene replacement strategies that are commonly employed for recessive, loss-of-function disorders are not readily translatable to most dominant myopathies owing to the presence of a normal chromosome in each nucleus, hindering the development of novel treatments for these dominant disorders. This is largely due to their complex, heterogeneous disease mechanisms that require unique therapeutic approaches. However, as viral and RNA interference-based therapies enter clinical use, key tools are now in place to develop treatments for dominantly inherited disorders of muscle. This article will review what is known about dominantly inherited disorders of muscle, specifically their genetic basis, how mutations lead to disease, and the pathomechanistic implications for therapeutic approaches.

Keywords: Dominant disease mechanisms; Dominant inheritance; Muscular dystrophy; Myopathy.

Fig. 1.

Patterns of inheritance of skeletal muscle disorders. (A) Autosomal dominant. (B) Autosomal recessive. (C) X-linked recessive. (D) X-linked dominant.

Fig. 2.

Patterns of muscle weakness encountered in dominantly inherited disorders of muscle. Red indicates normal muscles; blue indicates muscles that are weak. (A) Proximal weakness, as seen in limb-girdle muscular dystrophies (LGMDs). (B) Distal weakness, as seen in many myofibrillar myopathies. (C) Weakness seen in fascioscapulohumeral muscular dystrophy (FSHD). (D) Humeroperoneal pattern of weakness often seen in Emery-Dreifuss muscular dystrophies (EDMDs). (E) Weakness pattern seen in oculopharyngeal muscular dystrophy (OPMD). (F) Weakness pattern seen in oculopharyngeal distal myopathy (OPDM).

Fig. 3.

Dominant disease mechanisms. (A) Normal expression of protein. (B) Red represents mutations that reduce expression (i.e. nonsense, frameshift, etc.). Blue represents mutations that impact function (i.e. missense, in-frame deletion, etc.). Endogenous functioning proteins are colored gray and non-functioning proteins are colored blue. In disorders of haploinsufficiency, greater than 50% functioning protein is required to prevent disease. (C) Gain-of-function mechanisms refer to those involving increased protein levels (gene duplication or increased stability of mutant protein), hyperactivity of the mutant protein, or from misfolding of the mutant protein (purple) or RNA (green), creating aggregates that are toxic when not degraded. (D) Dominant-negative mechanisms are most easily illustrated in the case of proteins that form dimers or other multimeric structures. Any dimer that contains mutant protein (orange) is rendered non-functional. Assuming that each allele produces an equal amount of protein with equal stability, only 25% of dimers will be functional. Mut, mutant; WT, wild type. Republished with permission. The Creative Commons license does not apply to this content. Use of the material in any format is prohibited without written permission from the publisher, Wolters Kluwer Health, Inc.

Fig. 4.

Gene therapy approaches for dominant disease mechanisms. (A) Gene replacement therapy for dominant haploinsufficiency disorders due to reduced expression (red mutations) or loss of function (blue mutations). An AAV provides a functional copy of the gene (purple). (B-D) A variety of knockdown strategies may be used to treat dominant-negative or toxic, gain-of-function disorders. (B) Global knockdown of both WT (black) and mutant (black and orange) alleles is an ideal treatment strategy for dominant disorders if absence of the gene is not deleterious. One method for this is via siRNA or certain types of ASOs (green), which cause degradation of the target mRNA via recruitment of RISC or RNase, respectively. (C) Mutant allele-specific knockdown is preferred when knockout is deleterious but haploinsufficiency is tolerated. This can be achieved by designing siRNA (or other antisense knockdown technology) (green and orange), to preferentially bind to the mutant allele (black and orange). (D) In cases in which knockout and haploinsufficiency are both not tolerated, a knockdown-and-replace approach may be required. This can be achieved via viral delivery of RNAi (red) targeting both the WT allele (black) and mutant allele (black and orange) and simultaneous gene replacement using a codon optimized transgene (purple) to avoid knockdown. AAV, adeno-associated virus; ASO, antisense oligonucleotide; Mut, mutant; RISC, RNA-induced silencing complex; siRNA, small interfering RNA; WT, wild type. Republished with permission. The Creative Commons license does not apply to this content. Use of the material in any format is prohibited without written permission from the publisher, Wolters Kluwer Health, Inc.