Autosomal-Dominant Multiple Pterygium Syndrome Is Caused by Mutations in MYH3
2015; Elsevier BV; Volume: 96; Issue: 5 Linguagem: Inglês
10.1016/j.ajhg.2015.04.004
ISSN1537-6605
AutoresJessica X. Chong, Lindsay C. Burrage, Anita Beck, Colby T. Marvin, Margaret J. McMillin, Kathryn M. Shively, Tanya M. Harrell, Kati J. Buckingham, Carlos A. Bacino, Mahim Jain, Yasemin Alanay, Susan A. Berry, John C. Carey, Richard A. Gibbs, Brendan H. Lee, Deborah Krakow, Jay Shendure, Deborah A. Nickerson, Michael J. Bamshad, Michael J. Bamshad, Jay Shendure, Deborah A. Nickerson, Gonçalo R. Abecasis, Peter Anderson, Elizabeth Blue, Marcus Annable, Brian L. Browning, Kati J. Buckingham, Christina Chen, Jennifer Chin, Jessica X. Chong, Gregory M. Cooper, Colleen Davis, Christopher Frazar, Tanya M. Harrell, Zongxiao He, Preti Jain, Gail P. Jarvik, Guillaume Jimenez, Eric Johanson, Goo Jun, Martin Kircher, Tom Kolar, Stephanie Krauter, Niklas Krumm, Suzanne M. Leal, Daniel Luksic, Colby T. Marvin, Margaret J. McMillin, Sean McGee, Patrick O’Reilly, Bryan Paeper, Karynne Patterson, M. Lázaro Pérez, Sam W. Phillips, Jessica Pijoan, Christa Poel, Frédéric Reinier, Peggy D. Robertson, Regie Lyn P. Santos‐Cortez, Tristan Shaffer, Cindy Shephard, Kathryn M. Shively, Deborah L. Siegel, Joshua D. Smith, Jeffrey Staples, Holly K. Tabor, Monica Tackett, Jason G. Underwood, Marc Wegener, Gao Wang, Marsha M. Wheeler, Yi Qian,
Tópico(s)Mesenchymal stem cell research
ResumoMultiple pterygium syndrome (MPS) is a phenotypically and genetically heterogeneous group of rare Mendelian conditions characterized by multiple pterygia, scoliosis, and congenital contractures of the limbs. MPS typically segregates as an autosomal-recessive disorder, but rare instances of autosomal-dominant transmission have been reported. Whereas several mutations causing recessive MPS have been identified, the genetic basis of dominant MPS remains unknown. We identified four families affected by dominantly transmitted MPS characterized by pterygia, camptodactyly of the hands, vertebral fusions, and scoliosis. Exome sequencing identified predicted protein-altering mutations in embryonic myosin heavy chain (MYH3) in three families. MYH3 mutations underlie distal arthrogryposis types 1, 2A, and 2B, but all mutations reported to date occur in the head and neck domains. In contrast, two of the mutations found to cause MPS in this study occurred in the tail domain. The phenotypic overlap among persons with MPS, coupled with physical findings distinct from other conditions caused by mutations in MYH3, suggests that the developmental mechanism underlying MPS differs from that of other conditions and/or that certain functions of embryonic myosin might be perturbed by disruption of specific residues and/or domains. Moreover, the vertebral fusions in persons with MPS, coupled with evidence of MYH3 expression in bone, suggest that embryonic myosin plays a role in skeletal development. Multiple pterygium syndrome (MPS) is a phenotypically and genetically heterogeneous group of rare Mendelian conditions characterized by multiple pterygia, scoliosis, and congenital contractures of the limbs. MPS typically segregates as an autosomal-recessive disorder, but rare instances of autosomal-dominant transmission have been reported. Whereas several mutations causing recessive MPS have been identified, the genetic basis of dominant MPS remains unknown. We identified four families affected by dominantly transmitted MPS characterized by pterygia, camptodactyly of the hands, vertebral fusions, and scoliosis. Exome sequencing identified predicted protein-altering mutations in embryonic myosin heavy chain (MYH3) in three families. MYH3 mutations underlie distal arthrogryposis types 1, 2A, and 2B, but all mutations reported to date occur in the head and neck domains. In contrast, two of the mutations found to cause MPS in this study occurred in the tail domain. The phenotypic overlap among persons with MPS, coupled with physical findings distinct from other conditions caused by mutations in MYH3, suggests that the developmental mechanism underlying MPS differs from that of other conditions and/or that certain functions of embryonic myosin might be perturbed by disruption of specific residues and/or domains. Moreover, the vertebral fusions in persons with MPS, coupled with evidence of MYH3 expression in bone, suggest that embryonic myosin plays a role in skeletal development. Multiple pterygium syndrome (MPS) is a phenotypically and genetically heterogeneous group of rare Mendelian conditions characterized by multiple pterygia, scoliosis and congenital contractures of the limbs. Most often, MPS occurs as a simplex case, and of reported multiplex families, the majority consist of multiple affected siblings born to unaffected parents, consistent with inheritance in an autosomal-recessive pattern.1Vogt J. Morgan N.V. Rehal P. Faivre L. Brueton L.A. Becker K. Fryns J.P. Holder S. Islam L. Kivuva E. et al.CHRNG genotype-phenotype correlations in the multiple pterygium syndromes.J. Med. Genet. 2012; 49: 21-26Crossref PubMed Scopus (33) Google Scholar In very rare instances, MPS has been transmitted from an affected parent to an affected child, indicative of autosomal-dominant transmission.2Frias, J.L., Holahan, J.R., Rosenbloom, A.L., and Felman, A.H. (1973). An autosomal dominant syndrome of multiple pterygium, ptosis, and skeletal abnormalities. Proceedings of the Fourth International Conference on Birth Defects. Excerpta Medica 19.Google Scholar, 3Kawira E.L. Bender H.A. An unusual distal arthrogryposis.Am. J. Med. Genet. 1985; 20: 425-429Crossref PubMed Google Scholar, 4McKeown C.M. Harris R. An autosomal dominant multiple pterygium syndrome.J. Med. Genet. 1988; 25: 96-103Crossref PubMed Scopus (32) Google Scholar, 5Prontera P. Sensi A. Merlo L. Garani G. Cocchi G. Calzolari E. Familial occurrence of multiple pterygium syndrome: expression in a heterozygote of the recessive form or variability of the dominant form?.Am. J. Med. Genet. A. 2006; 140: 2227-2230Crossref PubMed Scopus (18) Google Scholar In 1996, we revised the classification of distal arthrogryposis (DA) syndromes and categorized several additional conditions,6Bamshad M. Jorde L.B. Carey J.C. A revised and extended classification of the distal arthrogryposes.Am. J. Med. Genet. 1996; 65: 277-281Crossref PubMed Scopus (183) Google Scholar including autosomal-dominant MPS, as DA syndromes because their clinical features overlap those of DA type 1 (DA1A [MIM: 108120] and DA1B [MIM: 614335]) and Freeman-Sheldon syndrome, or DA2A (MIM: 193700). Autosomal-dominant MPS, or DA8 (MIM: 178110), is one of the conditions that was added to the DA classification on the basis of the phenotypic features of four reported families in whom pterygia, camptodactyly of the hands, vertebral fusions, and scoliosis were transmitted from parent to child.2Frias, J.L., Holahan, J.R., Rosenbloom, A.L., and Felman, A.H. (1973). An autosomal dominant syndrome of multiple pterygium, ptosis, and skeletal abnormalities. Proceedings of the Fourth International Conference on Birth Defects. Excerpta Medica 19.Google Scholar, 3Kawira E.L. Bender H.A. An unusual distal arthrogryposis.Am. J. Med. Genet. 1985; 20: 425-429Crossref PubMed Google Scholar, 4McKeown C.M. Harris R. An autosomal dominant multiple pterygium syndrome.J. Med. Genet. 1988; 25: 96-103Crossref PubMed Scopus (32) Google Scholar, 5Prontera P. Sensi A. Merlo L. Garani G. Cocchi G. Calzolari E. Familial occurrence of multiple pterygium syndrome: expression in a heterozygote of the recessive form or variability of the dominant form?.Am. J. Med. Genet. A. 2006; 140: 2227-2230Crossref PubMed Scopus (18) Google Scholar Over the past decade, three previously unreported families with multiple persons who have clinical characteristics consistent with the diagnosis of DA8 and evidence of parent-to-child transmission were referred to our research program on DA syndromes (Table 1; Figures 1 and 2; Figure S1). To identify the gene(s) harboring mutations underlying DA8, we initially used Sanger sequencing to screen the proband of each family for mutations in genes known to contain mutations underlying lethal MPS (MIM: 253290) and non-lethal Escobar-variant autosomal-recessive MPS (MIM: 265000); these genes include CHRNG7Hoffmann K. Müller J.S. Stricker S. Mégarbané A. Rajab A. Lindner T.H. Cohen M. Chouery E. Adaimy L. Ghanem I. et al.Escobar syndrome is a prenatal myasthenia caused by disruption of the acetylcholine receptor fetal γ subunit.Am. J. Hum. Genet. 2006; 79: 303-312Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar, 8Morgan N.V. Brueton L.A. Cox P. Greally M.T. Tolmie J. Pasha S. Aligianis I.A. van Bokhoven H. Marton T. Al-Gazali L. et al.Mutations in the embryonal subunit of the acetylcholine receptor (CHRNG) cause lethal and Escobar variants of multiple pterygium syndrome.Am. J. Hum. Genet. 2006; 79: 390-395Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar (MIM: 100730), CHRND9Michalk A. Stricker S. Becker J. Rupps R. Pantzar T. Miertus J. Botta G. Naretto V.G. Janetzki C. Yaqoob N. et al.Acetylcholine receptor pathway mutations explain various fetal akinesia deformation sequence disorders.Am. J. Hum. Genet. 2008; 82: 464-476Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar (MIM: 100720), and CHRNA19Michalk A. Stricker S. Becker J. Rupps R. Pantzar T. Miertus J. Botta G. Naretto V.G. Janetzki C. Yaqoob N. et al.Acetylcholine receptor pathway mutations explain various fetal akinesia deformation sequence disorders.Am. J. Hum. Genet. 2008; 82: 464-476Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar (MIM: 100690), as well as IRF610Kondo S. Schutte B.C. Richardson R.J. Bjork B.C. Knight A.S. Watanabe Y. Howard E. de Lima R.L.L.F. Daack-Hirsch S. Sander A. et al.Mutations in IRF6 cause Van der Woude and popliteal pterygium syndromes.Nat. Genet. 2002; 32: 285-289Crossref PubMed Scopus (644) Google Scholar (MIM: 607199), mutations in which cause popliteal pterygium syndrome (MIM: 119500). No pathogenic mutations were found in any of these candidate genes. Next, we performed exome sequencing on seven individuals in family A, three individuals in family B, and two affected individuals (III-5 and V-2) in family C (Table 1; Figures 1 and 2; Figure S1). All studies were approved by the institutional review boards of the University of Washington and Seattle Children’s Hospital, and informed consent was obtained from each participant.Table 1Mutations in and Clinical Findings for Individuals with DA8Family AFamily BFamily CFamily DIII-1III-2II-2III-2II-1III-5aDescribed on the basis of a clinician’s report.IV-3V-2II-1I-1Mutation InformationMYH3 exon2525252525888no mutation identifiedno mutation identifiedcDNA changec.3214_3216dupc.3214_3216dupc.3214_3216dupc.3224A>Cc.3224A>Cc.727_729delc.727_729delc.727_729delNANAPredicted protein alterationp.Asn1072dupp.Asn1072dupp.Asn1072dupp.Gln1075Prop.Gln1075Prop.Ser243delp.Ser243delp.Ser243delNANAGERP score5.645.645.645.645.644.944.944.94NANACADD score v.1.1 (phred-like)17.6217.6217.6220.820.818.4718.4718.47NANAPolyPhen-2 score (HumVar)NANANA0.9310.931NANANANANAClinical Features: FaceDownslanting palpebral fissures+++++ND−−++Ptosis−+−++ND−−++Long nasal bridge+++++ND−−++Low-set, posteriorly rotated ears−−−++ND++++Clinical Features: LimbsHypoplastic flexion creases+++++ND++++Camptodactyly+++++ND++++Antecubital webbing−−−−+ND−+−−Elbow contractures+++++ND−+−−Limited forearm supination+++ND+NDNDND++Hip contracturesNDNDNDND+ND−ND+−Knee contractures−+++++++−−Popliteal webbing−++ND+ND++−−Foot contractures−−−−metatarsus adductusNDlimited ankle dorsiflexion−clubfeet−Other Clinical FeaturesScoliosis++−++++++−Short neck++++++++++Neck webbing−++++ND++++Short stature++−+ (<3rd percentile)+ ( 0.75], long homopolymer runs [HRun > 4], and/or low quality by depth [QD < 5]). Because DA8 is extremely rare (only four affected families have been reported to date2Frias, J.L., Holahan, J.R., Rosenbloom, A.L., and Felman, A.H. (1973). An autosomal dominant syndrome of multiple pterygium, ptosis, and skeletal abnormalities. Proceedings of the Fourth International Conference on Birth Defects. Excerpta Medica 19.Google Scholar, 3Kawira E.L. Bender H.A. An unusual distal arthrogryposis.Am. J. Med. Genet. 1985; 20: 425-429Crossref PubMed Google Scholar, 4McKeown C.M. Harris R. An autosomal dominant multiple pterygium syndrome.J. Med. Genet. 1988; 25: 96-103Crossref PubMed Scopus (32) Google Scholar, 5Prontera P. Sensi A. Merlo L. Garani G. Cocchi G. Calzolari E. Familial occurrence of multiple pterygium syndrome: expression in a heterozygote of the recessive form or variability of the dominant form?.Am. J. Med. Genet. A. 2006; 140: 2227-2230Crossref PubMed Scopus (18) Google Scholar), we excluded SNVs with an alternative allele frequency > 0.0001 in any population in the NHLBI Exome Sequencing Project Exome Variant Server dataset ESP6500, 1000 Genomes, the Exome Aggregation Consortium (ExAC v.1.0) Browser, or an internal database of ∼700 exomes. Additionally, SNVs that were flagged as low quality or potential false positives (QUAL ≤ 50, HRun > 4, QD < 5, presence within a cluster of SNPs) were also excluded from analysis. We generated copy-number variant (CNV) calls from exome data by using CoNIFER.11Krumm N. Sudmant P.H. Ko A. O’Roak B.J. Malig M. Coe B.P. Quinlan A.R. Nickerson D.A. Eichler E.E. NHLBI Exome Sequencing ProjectCopy number variation detection and genotyping from exome sequence data.Genome Res. 2012; 22: 1525-1532Crossref PubMed Scopus (430) Google Scholar Variants were annotated with the SeattleSeqAnnotation 138 server, and SNVs for which the only functional prediction label was “intergenic,” “coding-synonymous,” “utr,” “near-gene,” or “intron” were excluded. Individual genotypes with a depth < 6 or genotype quality < 20 were treated as missing in the analysis. To exclude known causes of MPS and well-known conditions that include pterygia, we first assessed the exome data for pathogenic variants in the genes previously screened by Sanger sequencing (IRF6, CHRNG, CHRNA1, and CHRND), as well as in RAPSN9Michalk A. Stricker S. Becker J. Rupps R. Pantzar T. Miertus J. Botta G. Naretto V.G. Janetzki C. Yaqoob N. et al.Acetylcholine receptor pathway mutations explain various fetal akinesia deformation sequence disorders.Am. J. Hum. Genet. 2008; 82: 464-476Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar, 12Vogt J. Harrison B.J. Spearman H. Cossins J. Vermeer S. ten Cate L.N. Morgan N.V. Beeson D. Maher E.R. Mutation analysis of CHRNA1, CHRNB1, CHRND, and RAPSN genes in multiple pterygium syndrome/fetal akinesia patients.Am. J. Hum. Genet. 2008; 82: 222-227Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar (MIM: 601592) and DOK713Vogt J. Morgan N.V. Marton T. Maxwell S. Harrison B.J. Beeson D. Maher E.R. Germline mutation in DOK7 associated with fetal akinesia deformation sequence.J. Med. Genet. 2009; 46: 338-340Crossref PubMed Scopus (51) Google Scholar (MIM: 610285). No SNVs or CNVs in these genes segregated with DA8 in any of the three families tested. Next, we looked for novel and/or rare SNVs and CNVs in the same gene shared among affected probands. No genes with rare or novel variants were shared among all three families. Affected individuals in families A and B were also screened for larger CNVs via array comparative genomic hybridization on the Illumina Infinium HumanCore-24 BeadChip. No shared or overlapping CNVs were identified. Subsequently, we loosened our filtering criteria to include variants in genes that were shared by two out of three families and identified three candidate genes (SHPRH [MIM: 608048], SLC5A9, and MYH3 [MIM: 160720]) in families A and B. The known functions of SHPRH and SLC5A9 appeared to be unrelated to the musculoskeletal phenotypes observed in all three families: SHPRH is involved in DNA repair and maintenance of genomic stability, and SLC5A9 encodes a sugar transporter primarily expressed in the small intestine and kidneys. In contrast, mutations in MYH3 frequently cause other forms of distal arthrogryposis, specifically DA2A and DA2B14Toydemir R.M. Rutherford A. Whitby F.G. Jorde L.B. Carey J.C. Bamshad M.J. Mutations in embryonic myosin heavy chain (MYH3) cause Freeman-Sheldon syndrome and Sheldon-Hall syndrome.Nat. Genet. 2006; 38: 561-565Crossref PubMed Scopus (187) Google Scholar (MIM: 601680) and, more rarely, DA1.15Alvarado D.M. Buchan J.G. Gurnett C.A. Dobbs M.B. Exome sequencing identifies an MYH3 mutation in a family with distal arthrogryposis type 1.J. Bone Joint Surg. Am. 2011; 93: 1045-1050Crossref PubMed Scopus (31) Google Scholar, 16Beck A.E. McMillin M.J. Gildersleeve H.I. Kezele P.R. Shively K.M. Carey J.C. Regnier M. Bamshad M.J. Spectrum of mutations that cause distal arthrogryposis types 1 and 2B.Am. J. Med. Genet. A. 2013; 161A: 550-555Crossref PubMed Scopus (47) Google Scholar In addition to having congenital contractures, persons with DA2A and DA2B variably have short stature, scoliosis, and infrequently, pterygia of the neck.17Stevenson D.A. Carey J.C. Palumbos J. Rutherford A. Dolcourt J. Bamshad M.J. Clinical characteristics and natural history of Freeman-Sheldon syndrome.Pediatrics. 2006; 117: 754-762Crossref PubMed Scopus (81) Google Scholar Accordingly, we considered MYH3 to be the most compelling candidate gene in these families. In MYH3 (GenBank: NM_002470.3), we specifically discovered variants c.3214_3216dup (p.Asn1072dup) in family A and c.3224A>C (p.Gln1075Pro) in family B. Both variants were subsequently validated via Sanger sequencing and found to segregate with only the affected persons in each family (Figure 2). Both variants affect highly conserved amino acid residues, have identical genomic evolutionary rate profiling (GERP) scores of 5.64, and are predicted to be deleterious by multiple methods (e.g., p.Asn1072dup has a combined annotation-dependent depletion [CADD]18Kircher M. Witten D.M. Jain P. O’Roak B.J. Cooper G.M. Shendure J. A general framework for estimating the relative pathogenicity of human genetic variants.Nat. Genet. 2014; 46: 310-315Crossref PubMed Scopus (3675) Google Scholar score of 17.62, and p.Gln1075Pro has a CADD score of 20.8). Moreover, neither variant was found in more than 71,000 total control exomes recorded in ESP6500, 1000 Genomes phase 1 (November 2010 release), internal databases (>1,400 chromosomes), and the ExAC Browser (October 20, 2014, release). Independently of the effort at the University of Washington to identify a gene associated with DA8, investigators at Baylor College of Medicine identified a five-generation family in whom ten persons were reported to be variably affected by a dominantly inherited condition characterized by short stature, scoliosis, multiple vertebral fusions, camptodactyly of the fingers, and multiple pterygia (Table 1; Figure S1), consistent with the diagnosis of DA8. Four individuals from this family were enrolled in a research protocol approved by the institutional review board at Baylor College of Medicine. Informed consent was obtained from each of these individuals prior to enrollment and prior to initiation of research studies. VCRome v.2.1 target-capture reagents (Roche Nimblegen) were used for performing whole-exome sequencing of DNA obtained from peripheral-blood monocytes from the proband (individual IV-3, Figure S1) and her father (individual III-5, Figure S1). 19Lupski J.R. Gonzaga-Jauregui C. Yang Y. Bainbridge M.N. Jhangiani S. Buhay C.J. Kovar C.L. Wang M. Hawes A.C. Reid J.G. et al.Exome sequencing resolves apparent incidental findings and reveals further complexity of SH3TC2 variant alleles causing Charcot-Marie-Tooth neuropathy.Genome Med. 2013; 5: 57Crossref PubMed Scopus (80) Google Scholar Sequencing was conducted on the Illumina HiSeq 2000 as previously described.19Lupski J.R. Gonzaga-Jauregui C. Yang Y. Bainbridge M.N. Jhangiani S. Buhay C.J. Kovar C.L. Wang M. Hawes A.C. Reid J.G. et al.Exome sequencing resolves apparent incidental findings and reveals further complexity of SH3TC2 variant alleles causing Charcot-Marie-Tooth neuropathy.Genome Med. 2013; 5: 57Crossref PubMed Scopus (80) Google Scholar Alignment, variant calling, and annotation were completed with the Mercury pipeline.20Reid J.G. Carroll A. Veeraraghavan N. Dahdouli M. Sundquist A. English A. Bainbridge M. White S. Salerno W. Buhay C. et al.Launching genomics into the cloud: deployment of Mercury, a next generation sequence analysis pipeline.BMC Bioinformatics. 2014; 15: 30Crossref PubMed Scopus (159) Google Scholar Comparison of exome sequence data from the proband and her affected father (Table 1; Figure S1) identified 46 shared rare variants (i.e., frequency < 0.0001 in ESP6500, 1000 Genomes phase 1 [November 2010 release], and the ExAC Browser [October 20, 2014, release]). No variants were identified in SHPRH or SLC5A9; however, one MYH3 variant not found in any other databases, c.727_729del (p.Ser243del), was found to affect a highly conserved amino acid residue (GERP score of 4.94) and was predicted to be highly deleterious (CADD v.1.1 score of 18.47). This variant was validated by Sanger sequencing and segregated in all of the affected individuals for whom DNA was available for testing. This variant was not observed in ESP6500, the ExAC Browser (v.0.3, January 13, 2015, release), or 1000 Genomes (October 2014 release). In 2006, we reported that mutations in MYH3 cause DA2A and DA2B.14Toydemir R.M. Rutherford A. Whitby F.G. Jorde L.B. Carey J.C. Bamshad M.J. Mutations in embryonic myosin heavy chain (MYH3) cause Freeman-Sheldon syndrome and Sheldon-Hall syndrome.Nat. Genet. 2006; 38: 561-565Crossref PubMed Scopus (187) Google Scholar Nevertheless, MYH3 was never considered a high-priority candidate gene in individuals with DA8 because affected individuals had multiple pterygia of the limbs, severe scoliosis, and vertebral fusions and did not have contractures of the facial muscles. More recently, we and others identified mutations in MYH3 in DA1-affected persons who had no facial contractures15Alvarado D.M. Buchan J.G. Gurnett C.A. Dobbs M.B. Exome sequencing identifies an MYH3 mutation in a family with distal arthrogryposis type 1.J. Bone Joint Surg. Am. 2011; 93: 1045-1050Crossref PubMed Scopus (31) Google Scholar, 16Beck A.E. McMillin M.J. Gildersleeve H.I. Kezele P.R. Shively K.M. Carey J.C. Regnier M. Bamshad M.J. Spectrum of mutations that cause distal arthrogryposis types 1 and 2B.Am. J. Med. Genet. A. 2013; 161A: 550-555Crossref PubMed Scopus (47) Google Scholar and DA2B-affected persons who had vertebral fusions and severe congenital scoliosis,21Beck A.E. McMillin M.J. Gildersleeve H.I. Shively K.M. Tang A. Bamshad M.J. Genotype-phenotype relationships in Freeman-Sheldon syndrome.Am. J. Med. Genet. A. 2014; 164A: 2808-2813Crossref PubMed Scopus (33) Google Scholar indicating that the phenotypic spectrum associated with MYH3 variants is broader than originally considered. This inference is now supported by our observation that variants in MYH3 cause DA8 and a wide range of phenotypic connective-tissue abnormalities, including congenital contractures, multiple pterygia, and bony fusions. MYH3 encodes muscle embryonic myosin heavy chain (MYH3), a skeletal-muscle myosin composed of a globular motor domain (amino acid residues ∼1–779) attached by short neck (∼779–840) and hinge (∼840) regions to a long coiled-coil rod domain (∼840–1,940). The majority of the rod region comprises the myosin tail domain (amino acid residues ∼1,070–1,940). Embryonic myosin exists as a dimer in which the tail domains are intertwined (Figure 3). Hundreds of myosin dimers assemble with one another and other proteins to form the thick filaments of the sarcomere, which is the subcellular contractile apparatus of cardiac-muscle and skeletal-muscle cells. All of the mutations known to cause DA1, DA2A, and DA2B16Beck A.E. McMillin M.J. Gildersleeve H.I. Kezele P.R. Shively K.M. Carey J.C. Regnier M. Bamshad M.J. Spectrum of mutations that cause distal arthrogryposis types 1 and 2B.Am. J. Med. Genet. A. 2013; 161A: 550-555Crossref PubMed Scopus (47) Google Scholar affect amino acid residues in the head and neck domains of embryonic myosin, whereas two of the three mutations that cause DA8 affect the tail domain. The clinical characteristics of the DA8-affected individuals with a mutation affecting the tail domain were more alike than the features of DA8-affected persons with a mutation affecting the head domain. This observation is limited, of course, by the fact that our dataset contained a small number of both families and individuals with DA8 caused by MYH3 mutations. Nevertheless, speculation on domain-specific, or at least domain-predominant, phenotypes has been reported previously for mutations in both muscle and non-muscle myosins. For example, mutations affecting the head domain of MYH9 (encoded by MYH9 [MIM: 160775]) cause severe thrombocytopenia and are associated with nephritis and deafness, whereas mutations affecting the tail domain cause less severe thrombocytopenia, such that median platelet counts are more than two times higher than those associated with head-domain mutations.22Pecci A. Panza E. Pujol-Moix N. Klersy C. Di Bari F. Bozzi V. Gresele P. Lethagen S. Fabris F. Dufour C. et al.Position of nonmuscle myosin heavy chain IIA (NMMHC-IIA) mutations predicts the natural history of MYH9-related disease.Hum. Mutat. 2008; 29: 409-417Crossref PubMed Scopus (143) Google Scholar Similarly, mutations throughout MYH7 (MIM: 160760) can cause hypertrophic (MIM: 192600) and/or dilated cardiomyopathy (MIM: 613426), whereas skeletal myopathies (e.g., myosin-storage myopathy [MIM: 608358] and Laing distal myopathy [MIM: 160500]) are caused almost exclusively by mutations affecting the tail domain of MYH7.23Tajsharghi H. Oldfors A. Myosinopathies: pathology and mechanisms.Acta Neuropathol. 2013; 125: 3-18Crossref PubMed Scopus (121) Google Scholar Moreover, mutations affecting the tail of MYH7 disrupt stability or self-assembly of sarcomere filaments or protein-protein interactions mediated through the tail, whereas mutations affecting the motor appear to alter the ATPase and actin-binding properties of myosin.24Armel T.Z. Leinwand L.A. Mutations in the beta-myosin rod cause myosin storage myopathy via multiple mechanisms.Proc. Natl. Acad. Sci. USA. 2009; 106: 6291-6296Crossref PubMed Scopus (37) Google Scholar This precedent of domain-specific phenotypic differences associated with mutations in other myosin-encoding genes suggests that similar genotype-phenotype relationships might exist in MYH3. Skeletal abnormalities have not commonly been observed, or at least reported, in persons with DA1, DA2A, or DA2B and with mutations in MYH3. Yet, skeletal defects were found in each of the three DA8-affected families carrying an MYH3 mutation in our study. The most common defects observed were vertebral abnormalities, including hemivertebrae and vertebral fusions of C1 and C2 or vertebrae of the thoracolumbar spine (Figure 2). A similar range of vertebral abnormali
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