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Embryonic Myosin Heavy-Chain Mutations Cause Distal Arthrogryposis and Developmental Myosin Myopathy That Persists Postnatally

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Embryonic Myosin Heavy-Chain Mutations Cause Distal Arthrogryposis and Developmental Myosin Myopathy That Persists Postnatally ORIGINAL CONTRIBUTION Embryonic Myosin Heavy-Chain Mutations Cause Distal Arthrogryposis and Developmental Myosin Myopathy That Persists Postnatally Homa Tajsharghi, PhD; Eva Kimber, MD; Anna-Karin Kroksmark, PhD; Ragnar Jerre, MD; Mar Tulinius, MD, PhD; Anders Oldfors, MD, PhD Background: Myosin is a molecular motor and the es- biopsy specimens were obtained, and in addition to mor- sential part of the thick filament of striated muscle. The phologic analysis, the expression of MyHC isoforms was expression of myosin heavy-chain (MyHC) isoforms is investigated at the protein and transcript levels. developmentally regulated. The embryonic isoform en- coded from MYH3 (OMIM *160720) is expressed dur- Results: We identified patients from 3 families with novel ing fetal life. Recently, mutations in MYH3 were demon- MYH3 mutations. These mutations affect developmen- strated to be associated with congenital joint contractures, tally conserved residues that are located in different re- that is, Freeman-Sheldon and Sheldon-Hall syndromes, gions of the adenosine triphosphate–binding pocket of which are both distal arthrogryposis syndromes. Muta- the MyHC head. The embryonic (MYH3) isoform was not tions in other MyHC isoforms cause myopathy. It is un- detected in any of the muscle biopsy samples, indicat- known whether MYH3 mutations cause myopathy be- ing a normal developmental downregulation of MYH3 in these patients. However, morphologic analysis of muscle cause muscle tissue has not been studied. biopsy specimens from the 4 patients revealed mild and Objectives: To determine whether novel MYH3 muta- variable myopathic features and a pathologic upregula- tions are associated with distal arthrogryposis and to dem- tion of the fetal MyHC isoform (MYH8) in 1 patient. onstrate myopathic changes in muscle biopsy speci- Conclusions: Distal arthrogryposis associated with MYH3 mens from 4 patients with distal arthrogryposis and MYH3 mutations is secondary to myosin myopathy, and post- mutations. natal muscle manifestations are variable. Design: In a cohort of patients with distal arthrogrypo- sis, we analyzed the entire coding sequence of MYH3. Muscle Arch Neurol. 2008;65(8):1083-1090 YOSIN IS THE MAIN COM- gressive muscle weakness. Mutations have ponent of skeletal been reported in 2 of 3 MyHC isoforms ex- muscle sarcomeric pressed in adult limb skeletal muscle. In thick filaments addition to familial hypertrophic or di- (Figure 1). It con- lated cardiomyopathy,11 mutations in the Msists of 2 globular heads attached to a long slow or ␤-cardiac MyHC gene (MYH7) ␣-helical–coiled coil rod domain. It is a cause skeletal myopathies such as myo- hexamer composed of 1 pair of myosin sin storage myopathy14-18 and Laing early- heavy chains (MyHCs) and 2 pairs of myo- onset distal myopathy.12,13 A mutation in sin light chains. The myosin globular head the MyHC IIa gene (MYH2) is associated Author Affiliations: domain of the myosin motor (myosin sub- with dominant myopathy characterized by Departments of Pathology (Drs Tajsharghi and Oldfors) fragment 1 [S1]) contains actin and aden- ophthalmoplegia, congenital joint con- and Orthopedics (Dr Jerre), osine triphosphate (ATP)–binding regions tractures, and rimmed vacuoles in muscle 7-9 Sahlgrenska University and is responsible for the force transduc- fibers. Recently, Freeman-Sheldon syn- Hospital; Departments of tion properties of myosin.1 Several striated drome and Sheldon-Hall syndrome, both Pediatrics, Institute for Clinical muscle MyHC genes have been de- distal arthrogryposis syndromes (DA2A Sciences, Sahlgrenska Academy scribed.2 The expression of myosin iso- and DA2B, respectively), have been re- at Go¨teborg University forms is developmentally regulated.3-5 ported as the first disorders associated with (Drs Kimber, Kroksmark, and Myosin myopathies have evolved as a mutations in embryonic MyHC (MYH3).10 Tulinius) and Queen Silvia’s new group of muscle diseases caused by Distal arthrogryposis syndromes are char- Children’s Hospital mutations in skeletal muscle myosin acterized by congenital contractures of at (Drs Kroksmark and Tulinius), 6 Go¨teborg; and Department of heavy-chain (MyHC) genes (Table 1). least 2 different body areas, with fre- Neuropediatrics, Uppsala The phenotypes of these diseases vary, quent involvement of the hands and feet, University Children´s Hospital, ranging from prenatal nonprogressive ar- but there may also be proximal joint Uppsala (Dr Kimber); Sweden. throgryposis syndromes to adult-onset pro- involvement.20,21 (REPRINTED) ARCH NEUROL / VOL 65 (NO. 8), AUG 2008 WWW.ARCHNEUROL.COM 1083 ©2008 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 A Z Z M B Tropomyosin Thick filament backbone (light meromyosin) Titin Myosin head (S1) Actin Troponin T Troponin I Troponin C Figure 1. Schematic illustration of the sarcomere. A, Electron micrograph of the skeletal muscle sarcomere. B, Schematic illustration of the sarcomere. Z- and M-bands are indicated. The thin filaments contain actin, tropomyosin, and troponin complex composed of troponins C, I, and T. The thick filaments are composed of myosin, with the globular heads forming cross-bridges with thin filaments and the light meromyosin, which constitutes the thick filament backbone and lies along the thick filament axis. Table 1. Diseases Associated With Mutations in Skeletal Muscle Myosin Heavy Chains Period of MyHC Muscle Expression in Gene Protein Fiber Type Skeletal Muscle3-5 Disease Major Clinical Characteristics References MYH2 MyHC IIa Type 2A From around Autosomal dominant myopathy Ophthalmoplegia, congenital 7-9 extraocular 24-wk with rimmed vacuoles, joint contractures, mild muscles gestational age ophthalmoplegia, and proximal muscle weakness in to adulthood congenital joint contractures childhood, and progressive course in adulthood MYH3 Embryonic MyHC Fetal development; From 6- to 24-wk Freeman-Sheldon syndrome Facial dysmorphism and 10 muscle gestational age; and Sheldon-Hall syndrome congenital joint contractures regeneration completely with predominant distal eliminated by involvement (distal 37-wk arthrogryposis) gestational age Familial hypertrophic or dilated Cardiac failure or sudden 11 cardiomyopathy cardiac death MYH7 MyHC I (slow) Skeletal muscle From 6- to 14-wk Laing early-onset distal Onset of muscle weakness in 12,13 (␤-cardiac type 1 (heart gestational age myopathy childhood; slowly progressive MyHC) ventricles) to adulthood with initial weakness of ankle dorsiflexion; rarely cardiomyopathy Myosin storage myopathy Onset from childhood to middle 14-18 age; weakness of limb girdle, scapuloperoneal, or distal muscles; mild or severe weakness affecting ambulation; rarely cardiomyopathy MYH8 Perinatal MyHC Fetal development; From 7- to 15-wk Trismus and Congenital contractures of 19 muscle gestational age pseudocamptodactyly hands, feet, and jaws with regeneration to around birth syndrome trismus and hand and foot deformities with pseudocamptodactyly (REPRINTED) ARCH NEUROL / VOL 65 (NO. 8), AUG 2008 WWW.ARCHNEUROL.COM 1084 ©2008 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 Distal arthrogryposis syndromes are associated with (Figure 2). Patient 3 was a man with a milder form of missense mutations in various genes coding for sarco- DA2B. The clinical features included contractures, primarily meric proteins. The genes thus far demonstrated to be in the hands, with mild involvement of the jaws, feet, and involved in distal arthrogryposis syndromes are TNNI2 elbows, and normal muscle strength (Figure 3). No (troponin I) (OMIM *191043),22,23 TPM2 (␤- involvement of the shoulder joints was noted. He had 3 chil- dren who all had signs of distal arthrogryposis. Patient 4 had tropomyosin) (OMIM *190990),23,24 TNNT3 (troponin 25 sporadic DA2A with ptosis, very short stature, small and T) (OMIM *606092), MYH8 (perinatal MyHC) (OMIM contracted mouth, and joint contractures in the proximal 19 10 *160741), and MYH3 (embryonic MyHC). These find- and distal joints. Joint involvement included the ankles and ings indicate that distal arthrogryposis syndromes are feet. Muscle strength was difficult to evaluate owing to caused by myopathies with onset during fetal develop- young age, which was 4 years at the last assessment. ment, but few studies have involved analysis of muscle tissue in these diseases.22,24,26 In this article, we report novel GENETIC ANALYSES MYH3 mutations associated with distal arthrogryposis and demonstrate myopathic changes in muscle biopsy speci- Extraction of genomic DNA, sequence analysis, and the mens from 4 patients with distal arthrogryposis and MYH3 polymerase chain reaction were performed as previously mutations. described.22 The entire coding sequence of MYH3 was sequenced using previously described primers.10 The pres- ence of each mutation was confirmed in each affected indi- METHODS vidual at restriction fragment length polymorphism analysis (Table 2). The restriction fragment length polymorphism PATIENTS was also used to screen for the presence of each mutation in 200 control chromosomes. In addition to MYH3, the entire Patients 1 and 2 were mother and daughter with DA2B. The coding region of the TPM2, TNNI2, TNNT3, TNNI1 (OMIM clinical features included short stature, scoliosis, mild facial *191042), TNNT1 (OMIM *191041), TNNC1 (OMIM dysmorphism, decreased muscle strength, and contractures *191040), and TNNC2 (OMIM *191039) genes was in proximal and distal joints
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