Mutations inMYLPFcause a novel segmental amyoplasia that manifests as distal arthrogryposis

Abstract

Mutations in MYLPF cause a novel segmental amyoplasia that manifests as distal1 arthrogryposis 2 3 Abstract 72 We identified ten persons in six consanguineous families with Distal Arthrogryposis (DA) who 73 had congenital contractures, scoliosis, and short stature. Exome sequencing revealed that each 74 affected person was homozygous for one of two different rare variants (c.470G>T, 75 p.(Cys157Phe) or c.469T>C, p.(Cys157Arg)) affecting the same residue of myosin light chain, 76 phosphorylatable, fast skeletal muscle (MYLPF). In a seventh family, a c.487G>A, 77 p.(Gly163Ser) variant in MYLPF arose de novo in a father, who transmitted it to his son. In an 78 eighth family comprised of seven individuals with dominantly-inherited DA, a c.98C>T, 79 p.(Ala33Val) variant segregated in all four persons tested. Variants in MYLPF underlie both 80 dominant and recessively inherited DA. Mylpf protein models suggest that the residues 81 associated with dominant DA interact with myosin whereas the residues altered in families with 82 recessive DA only indirectly impair this interaction. Pathological and histological exam of a foot 83 amputated from an affected child revealed complete absence of skeletal muscle (i.e., segmental 84 amyoplasia). To investigate the mechanism for this finding, we generated an animal model for 85 partial MYLPF impairment by knocking out zebrafish mylpfa. The mylpfa mutant had reduced 86 trunk contractile force and complete pectoral fin paralysis, demonstrating that mylpf impairment 87 most severely affects limb movement. mylpfa mutant muscle weakness was most pronounced 88 in an appendicular muscle and was explained by reduced myosin activity and fiber 89 degeneration. Collectively, our findings demonstrate that partial loss of MYLPF function can 90 lead to congenital contractures, likely as a result of degeneration of skeletal muscle in the distal 91 limb. 92 93 94 KEYWORDS 95 exome sequencing, Mendelian disease, congenital contractures, distal arthrogryposis, 96 amyoplasia, development, skeletal muscle, zebrafish 97 100 DAs are characterized by non-progressive congenital contractures of the limbs, most commonly 101 affecting the hands, wrists, feet, and ankles. Congenital contractures of the face, ocular 102 muscles, neck webbing, pterygia, short stature, and scoliosis are less frequent, variable findings 103 that facilitate delineation among the most common DA conditions: DA1 2 (MIM 108120), DA2A 3 104 (Freeman-Sheldon syndrome [MIM 193700]) and DA2B 4 (Sheldon-Hall syndrome [601680]). 105 Variants in any one of sixteen different genes can underlie DA but the overwhelming majority of 106 known pathogenic variants occur in just five genes (TPM2 (MIM 190990), TNNI2 (MIM 191043), 107 TNNT3 (MIM 600692), MYH3 (MIM 160720), MYH8 (MIM 160741)). 5,6 Yet, collectively 108 pathogenic variants are identified in only ~60% of families diagnosed with a DA, so the precise 109 genetic etiology remains unknown in nearly half of DA families. 110 Most of the genes that underlie DA encode sarcomeric components of ...