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Expanding the mutat...
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Zhao, SenDepartment of Orthopedic Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China; Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, China,Peking Union Med Coll, Peoples R China; Chinese Acad Med Sci, Peoples R China; Beijing Key Lab Genet Res Skeletal Deform, Peoples R China
(author)
Expanding the mutation and phenotype spectrum of MYH3-associated skeletal disorders
- Article/chapterEnglish2022
Publisher, publication year, extent ...
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2022-02-15
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Nature Publishing Group,2022
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printrdacarrier
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LIBRIS-ID:oai:DiVA.org:oru-97571
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https://urn.kb.se/resolve?urn=urn:nbn:se:oru:diva-97571URI
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https://doi.org/10.1038/s41525-021-00273-xDOI
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https://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-183218URI
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http://kipublications.ki.se/Default.aspx?queryparsed=id:148871547URI
Supplementary language notes
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Language:English
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Summary in:English
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Subject category:ref swepub-contenttype
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Subject category:art swepub-publicationtype
Notes
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Funding agency:National Natural Science Foundation of China (NSFC) 81930068 81772299 81822030 82072391 81972132 81672123 81972037 81902178Beijing Natural Science Foundation JQ20032 7191007 CAMS Innovation Fund for Medical Sciences (CIFMS) 2021-I2M-1-051 2021-I2M-1-052Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences 2019PT320025Tsinghua University-Peking Union Medical College Hospital Initiative Scientific Research ProgramPUMC Youth Fund & the Fundamental Research Funds for the Central Universities 3332019021Byggmästare Olle Engkvist StiftelseNyckelfondenÖrebro University, Örebro, SwedenSällskapet BarnavårdStiftelsen SällsyntafondenUS National Institutes of Health (NIH), National Institute of Neurological Disorders and Stroke NINDS R35 NS105078National Human Genome Research Institute/National Heart, Lung, and Blood Institute NHGRI/NHLBI UM1 HG006542US NIH National Human Genome Research Institute NHGRI K08 HG008986
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Funding Agencies|National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81930068, 81772299, 81822030, 82072391, 81972132, 81672123, 81972037, 81902178]; Beijing Natural Science FoundationBeijing Natural Science Foundation [JQ20032, 7191007]; CAMS Innovation Fund for Medical Sciences (CIFMS) [2021-I2M-1-051, 2021-I2M-1-052]; Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences [2019PT320025]; Tsinghua University-Peking Union Medical College Hospital Initiative Scientific Research Program; PUMC Youth Fund & the Fundamental Research Funds for the Central Universities [3332019021]; Swedish Research CouncilSwedish Research CouncilEuropean Commission [K2015-54X-22 736-01-4, 2015-02227, 2018-03046]; Swedish Governmental Agency for Innovation Systems (Vinnova)Vinnova [2014-01438]; Marianne and Marcus Wallenberg Foundation; IngaBritt och Arne Lundbergs forskningsstiftelse; Byggmastare Olle Engkvist Stiftelse; Promobilia; Nyckelfonden; Stiftelsen Frimurare Barnhuset i Stockholm; Region Stockholm; Karolinska Institutet, Stockholm, Sweden; orebro University, orebro, Sweden; Sallskapet Barnavard; Karolinska InstitutetKarolinska Institutet; Stiftelsen Sallsyntafonden; Stiftelsen Samariten; Stiftelsen Promobilia; Region Stockholm [20180131, 20200500]; US National Institutes of Health (NIH), National Institute of Neurological Disorders and Stroke [NINDS R35 NS105078]; National Human Genome Research Institute/National Heart, Lung, and Blood Institute [NHGRI/NHLBI UM1 HG006542]; US NIH National Human Genome Research Institute [NHGRI K08 HG008986]
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Pathogenic variants in MYH3 cause distal arthrogryposis type 2A and type 2B3 as well as contractures, pterygia and spondylocarpotarsal fusion syndromes types 1A and 1B. These disorders are ultra-rare and their natural course and phenotypic variability are not well described. In this study, we summarize the clinical features and genetic findings of 17 patients from 10 unrelated families with vertebral malformations caused by dominant or recessive pathogenic variants in MYH3. Twelve novel pathogenic variants in MYH3 (NM_002470.4) were identified: three of them were de novo or inherited in autosomal dominant way and nine were inherited in autosomal recessive way. The patients had vertebral segmentation anomalies accompanied with variable joint contractures, short stature and dysmorphic facial features. There was a significant phenotypic overlap between dominant and recessive MYH3-associated conditions regarding the degree of short stature as well as the number of vertebral fusions. All monoallelic variants caused significantly decreased SMAD3 phosphorylation, which is consistent with the previously proposed pathogenic mechanism of impaired canonical TGF-β signaling. Most of the biallelic variants were predicted to be protein-truncating, while one missense variant c.4244T>G,p.(Leu1415Arg), which was inherited in an autosomal recessive way, was found to alter the phosphorylation level of p38, suggesting an inhibition of the non-canonical pathway of TGF-β signaling. In conclusion, the identification of 12 novel pathogenic variants and overlapping phenotypes in 17 affected individuals from 10 unrelated families expands the mutation and phenotype spectrum of MYH3-associated skeletal disorders. We show that disturbances of canonical or non-canonical TGF-β signaling pathways are involved in pathogenesis of MYH3-associated skeletal fusion (MASF) syndrome.
Subject headings and genre
Added entries (persons, corporate bodies, meetings, titles ...)
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Zhang, YuanqiangDepartment of Orthopedic Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China; Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, China; Department of Orthopaedic Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China,Peking Union Med Coll, Peoples R China; Chinese Acad Med Sci, Peoples R China; Beijing Key Lab Genet Res Skeletal Deform, Peoples R China; Shandong Univ, Peoples R China
(author)
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Hallgrimsdottir, SigrunDivision of Pediatric Endocrinology and Center for Molecular Medicine, Department of Women's and Children's Health, Karolinska Institutet and University Hospital, Stockholm, Sweden,Karolinska Inst, Sweden; Karolinska Inst, Sweden; Univ Hosp, Sweden
(author)
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Zuo, YuzhiDepartment of Orthopedic Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China; Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, China,Peking Union Med Coll, Peoples R China; Chinese Acad Med Sci, Peoples R China; Beijing Key Lab Genet Res Skeletal Deform, Peoples R China
(author)
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Li, XiaoxinBeijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, China; Key laboratory of big data for spinal deformities, Chinese Academy of Medical Sciences, Beijing, China,Beijing Key Lab Genet Res Skeletal Deform, Peoples R China; Chinese Acad Med Sci, Peoples R China
(author)
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Batkovskyte, DominykaKarolinska Institutet
(author)
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Liu, SenDepartment of Orthopedic Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China; Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, China,Peking Union Med Coll, Peoples R China; Chinese Acad Med Sci, Peoples R China; Beijing Key Lab Genet Res Skeletal Deform, Peoples R China
(author)
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Lindelöf, HilleviKarolinska Institutet
(author)
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Wang, ShengruDepartment of Orthopedic Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China,Peking Union Med Coll, Peoples R China; Chinese Acad Med Sci, Peoples R China
(author)
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Hammarsjö, AnnaKarolinska Institutet
(author)
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Yang, YangDepartment of Orthopedic Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China,Peking Union Med Coll, Peoples R China; Chinese Acad Med Sci, Peoples R China; Beijing Key Lab Genet Res Skeletal Deform, Peoples R China; Shandong Univ, Peoples R China
(author)
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Ye, YongyuDepartment of Joint Surgery, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China,Sun Yat Sen Univ, Peoples R China
(author)
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Wang, LianleiDepartment of Orthopedic Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China; Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, China; Department of Orthopaedic Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
(author)
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Yan, ZihuiDepartment of Orthopedic Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China; Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, China
(author)
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Lin, JiachenDepartment of Orthopedic Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China; Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, China,Peking Union Med Coll, Peoples R China; Chinese Acad Med Sci, Peoples R China; Beijing Key Lab Genet Res Skeletal Deform, Peoples R China
(author)
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Yu, ChenxiDepartment of Orthopedic Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China; Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, China,Peking Union Med Coll, Peoples R China; Chinese Acad Med Sci, Peoples R China; Beijing Key Lab Genet Res Skeletal Deform, Peoples R China
(author)
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Chen, ZefuDepartment of Orthopedic Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China; Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, China,Peking Union Med Coll, Peoples R China; Chinese Acad Med Sci, Peoples R China; Beijing Key Lab Genet Res Skeletal Deform, Peoples R China
(author)
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Niu, YuchenBeijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, China; Key laboratory of big data for spinal deformities, Chinese Academy of Medical Sciences, Beijing, China,Beijing Key Lab Genet Res Skeletal Deform, Peoples R China; Chinese Acad Med Sci, Peoples R China
(author)
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Wang, HuiziBeijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, China; Key laboratory of big data for spinal deformities, Chinese Academy of Medical Sciences, Beijing, China
(author)
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Zhao, ZhiBeijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, China; Key laboratory of big data for spinal deformities, Chinese Academy of Medical Sciences, Beijing, China,Beijing Key Lab Genet Res Skeletal Deform, Peoples R China; Chinese Acad Med Sci, Peoples R China
(author)
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Liu, PengfeiDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Baylor Genetics, Houston, TX, USA,Baylor Coll Med, TX 77030 USA; Baylor Genet, TX 77021 USA
(author)
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Qiu, GuixingDepartment of Orthopedic Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China; Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, China; Key laboratory of big data for spinal deformities, Chinese Academy of Medical Sciences, Beijing, China,Peking Union Med Coll, Peoples R China; Chinese Acad Med Sci, Peoples R China; Beijing Key Lab Genet Res Skeletal Deform, Peoples R China; Chinese Acad Med Sci, Peoples R China
(author)
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Posey, Jennifer E.Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA,Baylor Coll Med, TX 77030 USA
(author)
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Wu, ZhihongBeijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, China; Key laboratory of big data for spinal deformities, Chinese Academy of Medical Sciences, Beijing, China,Beijing Key Lab Genet Res Skeletal Deform, Peoples R China; Chinese Acad Med Sci, Peoples R China
(author)
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Lupski, James R.Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Departments of Pediatrics, Texas Children's Hospital and Baylor College of Medicine, Houston, TX, USA; Texas Children's Hospital, Houston, TX, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA,Baylor Coll Med, TX 77030 USA; Texas Childrens Hosp, TX 77030 USA; Baylor Coll Med, TX 77030 USA; Texas Childrens Hosp, TX 77030 USA; Baylor Coll Med, TX 77030 USA
(author)
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Micule, IevaClinic of Medical Genetics and Prenatal Diagnostics, Children's Clinical University Hospital, Riga, Latvia,Childrens Clin Univ Hosp, Latvia
(author)
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Anderlid, Britt-MarieKarolinska Institutet
(author)
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Voss, UlrikaDepartment of Pediatric Radiology, Karolinska University Hospital, Stockholm, Sweden,Karolinska Univ Hosp, Sweden
(author)
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Sulander, DennisLinköpings universitet,Avdelningen för cellbiologi,Medicinska fakulteten,Region Östergötland, Klinisk genetik(Swepub:liu)densu45
(author)
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Kuchinskaya, EkaterinaLinköpings universitet,Avdelningen för cellbiologi,Medicinska fakulteten,Region Östergötland, Klinisk genetik(Swepub:liu)ekaku57
(author)
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Nordgren, AnnKarolinska Institutet
(author)
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Nilsson, Ola,1970-Karolinska Institutet,Örebro universitet,Institutionen för medicinska vetenskaper,Division of Pediatric Endocrinology and Center for Molecular Medicine, Department of Women's and Children's Health, Karolinska Institutet and University Hospital, Stockholm, Sweden; Department of Pediatrics, Örebro University Hospital, Örebro, Sweden,Karolinska Inst, Sweden; Karolinska Inst, Sweden; Univ Hosp, Sweden; Orebro Univ, Sweden; Orebro Univ Hosp, Sweden(Swepub:oru)oann
(author)
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Zhang, Terry JianguoDepartment of Orthopedic Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China; Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, China; Key laboratory of big data for spinal deformities, Chinese Academy of Medical Sciences, Beijing, China,Peking Union Med Coll, Peoples R China; Chinese Acad Med Sci, Peoples R China; Beijing Key Lab Genet Res Skeletal Deform, Peoples R China; Chinese Acad Med Sci, Peoples R China
(author)
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Grigelioniene, GiedreKarolinska Institutet
(author)
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Wu, NanDepartment of Orthopedic Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China; Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, China; Key laboratory of big data for spinal deformities, Chinese Academy of Medical Sciences, Beijing, China; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA,Peking Union Med Coll, Peoples R China; Chinese Acad Med Sci, Peoples R China; Beijing Key Lab Genet Res Skeletal Deform, Peoples R China; Chinese Acad Med Sci, Peoples R China; Baylor Coll Med, TX 77030 USA
(author)
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Department of Orthopedic Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China; Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, ChinaPeking Union Med Coll, Peoples R China; Chinese Acad Med Sci, Peoples R China; Beijing Key Lab Genet Res Skeletal Deform, Peoples R China
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