Project

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Molecular basis of human skeletal dysplasias

English title Molecular basis of human skeletal dysplasias
Applicant Bonafé Luisa
Number 132940
Funding scheme Project funding (Div. I-III)
Research institution Division de Pédiatrie Moléculaire Centre Hospitalier Universitaire Vaudois
Institution of higher education University of Lausanne - LA
Main discipline Genetics
Start/End 01.10.2010 - 30.09.2014
Approved amount 331'000.00
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All Disciplines (2)

Discipline
Genetics
Embryology, Developmental Biology

Keywords (7)

skeletal dysplasia; proteoglycan; knockout mouse; linkage analysis; growth plate; endochondral ossification; short stature

Lay Summary (English)

Lead
Lay summary
Skeletal dysplasias are genetic disorders of skeletal development and growth. They are characterized by severe short stature, deformity, and various complications such as chronic joint pain and disabilities in daily life. There are more than 200 different genetic skeletal dysplasias and only a limited part of the genes mutated in these conditions is known. The broader aim of our research is to gain information on the molecular mechanisms underlying skeletal dysplasias in humans.The project focuses on three skeletal disorders, all characterized by marked short stature.The first one (Omodysplasia) is a developmental defect of long bones; we have previously identified the gene mutated in this disorder, which encode for a proteoglycan with a probable function on long-bone growth regulation (glypican 6). For Omodysplasia, the specific aim is to understand the function of glypican 6 in bone and cartilage, through the generation and study of a knockout mouse for the GPC6 gene.The other two disorders (SPONASTRIME dysplasia and Spondylo-Epi-Metaphyseal Dysplasia with Joint Laxitiy, Leptodactylic type) are spondylo-metaphyseal dysplasias with different degree of severity and joint involvement. The specific aims of the project are the identification of the genes mutated in these skeletal dysplasias and the understanding of the molecular mechanisms underlying the different phenotypic features. These aims will be approached using a combination of positional cloning (gene mapping by high density SNPs microarrays) and new-generation sequencing techniques (exon capturing and high-throughput sequencing).We expect the research results to be valuable at different levels. Gaining molecular information on genetic skeletal disorders will provide reliable diagnostic tests for genetic counseling, establish the biological basis for appropriate management of affected children and their families, and hopefully reveal some pathogenetic steps that might prove amenable to pharmacological therapy. The results shall shed light on the biological aspects of morphogenesis, development, growth, and homeostasis of the skeleton. Understanding the biology of bone and cartilage in rare disorders will provide insights on more common diseases, such as arthritis, osteoporosis and short stature.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Eight years experience from a skeletal dysplasia referral center in a tertiary hospital in Southern India: a model for the diagnosis and treatment of rare diseases in a developing country.
Nampoothiri Sheela, Yesodharan Dhanya, Sainulabdin Gazel, Narayanan Dhanyalakshmi, Padmanabhan Laxmi, Girisha Katta Mohan, Cathey Sara S, De Paepe Anne, Malfait Fransiska, Syx Delfien, Hennekam Raoul C, Bonafe Luisa, Unger Sheila, Superti-Furga Andrea (2014), Eight years experience from a skeletal dysplasia referral center in a tertiary hospital in Southern India: a model for the diagnosis and treatment of rare diseases in a developing country., in American journal of medical genetics. Part A, 164A(9), 2317-23.
MMP13 Mutations are the Cause of Recessive Metaphyseal Dysplasia, Spahr Type
Bonafe Luisa, Liang Jinlong, Gorna Maria W., Zhang Qingyan, Ha-Vinh Russia, Campos-Xavier Ana Belinda, Unger Sheila, Beckmann Jacques S., Le Bechec Antony, Stevenson Brian, Giedion Andres, Liu Xuanzhu, Superti-Furga Giulio, Wang Wei, Spahr Andre, Superti-Furga Andrea (2014), MMP13 Mutations are the Cause of Recessive Metaphyseal Dysplasia, Spahr Type, in AMERICAN JOURNAL OF MEDICAL GENETICS PART A, 164(5), 1175-1179.
Positive effects of an angiotensin II type 1 receptor antagonist in Camurati-Engelmann disease: a single case observation.
Simsek-Kiper Pelin Ozlem, Dikoglu Esra, Campos-Xavier Belinda, Utine Gulen Eda, Bonafe Luisa, Unger Sheila, Boduroglu Koray, Superti-Furga Andrea (2014), Positive effects of an angiotensin II type 1 receptor antagonist in Camurati-Engelmann disease: a single case observation., in American journal of medical genetics. Part A, 164A(10), 2667-71.
FAM111A Mutations Result in Hypoparathyroidism and Impaired Skeletal Development
Unger Sheila, Gorna Maria W., Le Bechec Antony, Do Vale-Pereira Sonia, Bedeschi Maria Francesca, Geiberger Stefan, Grigelioniene Giedre, Horemuzova Eva, Lalatta Faustina, Lausch Eldehart, Magnan Cinzia, Nampoothiri Sheela, Nishimura Gen, Petrella Duccio, Rojas-Ringeling Francisca, Utsunomiya Akari, Zabel Bernhard, Pradervand Sylvain, Harshman Keith, Campos-Xavier Belinda, Bonafe Luisa, Superti-Furga Giulio, Stevenson Brian, Superti-Furga Andrea (2013), FAM111A Mutations Result in Hypoparathyroidism and Impaired Skeletal Development, in AMERICAN JOURNAL OF HUMAN GENETICS, 92(6), 990-995.
Homozygosity for a novel truncating mutation confirms TBX15 deficiency as the cause of Cousin syndrome.
Dikoglu Esra, Simsek-Kiper Pelin Ozlem, Utine Gulen Eda, Campos-Xavier Belinda, Boduroglu Koray, Bonafé Luisa, Superti-Furga Andrea, Unger Sheila (2013), Homozygosity for a novel truncating mutation confirms TBX15 deficiency as the cause of Cousin syndrome., in American journal of medical genetics. Part A, 161A(12), 3161-5.
Mutations in B3GALT6, which Encodes a Glycosaminoglycan Linker Region Enzyme, Cause a Spectrum of Skeletal and Connective Tissue Disorders
Nakajima Masahiro, Mizumoto Shuji, Miyake Noriko, Kogawa Ryo, Iida Aritoshi, Ito Hironori, Kitoh Hiroshi, Hirayama Aya, Mitsubuchi Hiroshi, Miyazaki Osamu, Kosaki Rika, Horikawa Reiko, Lai Angeline, Mendoza-Londono Roberto, Dupuis Lucie, Chitayat David, Howard Andrew, Leal Gabriela E., Cavalcanti Denise, Tsurusaki Yoshinori, Saitsu Hirotomo, Watanabe Shigehiko, Lausch Ekkehart, Unger Sheila, Bonafe Luisa (2013), Mutations in B3GALT6, which Encodes a Glycosaminoglycan Linker Region Enzyme, Cause a Spectrum of Skeletal and Connective Tissue Disorders, in AMERICAN JOURNAL OF HUMAN GENETICS, 92(6), 927-934.
Post-axial polydactyly type A2, overgrowth and autistic traits associated with a chromosome 13q31.3 microduplication encompassing miR-17-92 and GPC5
Kannu P., Campos-Xavier A. B., Hull D., Martinet D., Ballhausen D., Bonafe L. (2013), Post-axial polydactyly type A2, overgrowth and autistic traits associated with a chromosome 13q31.3 microduplication encompassing miR-17-92 and GPC5, in EUROPEAN JOURNAL OF MEDICAL GENETICS, 56(8), 452-457.
Extracellular matrix and platelet function in patients with musculocontractural Ehlers-Danlos syndrome caused by mutations in the CHST14 gene.
Mendoza-Londono Roberto, Chitayat David, Kahr Walter H A, Hinek Aleksander, Blaser Susan, Dupuis Lucie, Goh Elaine, Badilla-Porras Ramses, Howard Andrew, Mittaz Laureane, Superti-Furga Andrea, Unger Sheila, Nishimura Gen, Bonafe Luisa (2012), Extracellular matrix and platelet function in patients with musculocontractural Ehlers-Danlos syndrome caused by mutations in the CHST14 gene., in American journal of medical genetics. Part A, 158A(6), 1344-54.
New topics in the skeletal dysplasias.
Unger Sheila, Bonafé Luisa, Superti-Furga Andrea (2012), New topics in the skeletal dysplasias., in American journal of medical genetics. Part C, Seminars in medical genetics, 160C(3), 143-4.
Severe neurologic manifestations from cervical spine instability in spondylo-megaepiphyseal-metaphyseal dysplasia.
Simon Marleen, Campos-Xavier Ana Belinda, Mittaz-Crettol Lauréane, Valadares Eugenia Ribeiro, Carvalho Daniel, Speck-Martins Carlos Eduardo, Nampoothiri Sheela, Alanay Yasemin, Mihci Ercan, van Bever Yolande, Garcia-Segarra Nuria, Cavalcanti Denise, Mortier Geert, Bonafé Luisa, Superti-Furga Andrea (2012), Severe neurologic manifestations from cervical spine instability in spondylo-megaepiphyseal-metaphyseal dysplasia., in American journal of medical genetics. Part C, Seminars in medical genetics, 160C(3), 230-7.
The diagnostic challenge of progressive pseudorheumatoid dysplasia (PPRD): a review of clinical features, radiographic features, and WISP3 mutations in 63 affected individuals.
Garcia Segarra Nuria, Mittaz Laureane, Campos-Xavier Ana Belinda, Bartels Cynthia F, Tuysuz Beyhan, Alanay Yasemin, Cimaz Rolando, Cormier-Daire Valerie, Di Rocco Maja, Duba Hans-Christoph, Elcioglu Nursel H, Forzano Francesca, Hospach Toni, Kilic Esra, Kuemmerle-Deschner Jasmin B, Mortier Geert, Mrusek Sonja, Nampoothiri Sheela, Obersztyn Ewa, Pauli Richard M, Selicorni Angelo, Tenconi Romano, Unger Sheila, Utine G Eda, Wright Michael (2012), The diagnostic challenge of progressive pseudorheumatoid dysplasia (PPRD): a review of clinical features, radiographic features, and WISP3 mutations in 63 affected individuals., in American journal of medical genetics. Part C, Seminars in medical genetics, 160C(3), 217-29.
Chondrodysplasia and abnormal joint development associated with mutations in IMPAD1, encoding the Golgi-resident nucleotide phosphatase, gPAPP.
Vissers Lisenka E L M, Lausch Ekkehart, Unger Sheila, Campos-Xavier Ana Belinda, Gilissen Christian, Rossi Antonio, Del Rosario Marisol, Venselaar Hanka, Knoll Ute, Nampoothiri Sheela, Nair Mohandas, Spranger Jürgen, Brunner Han G, Bonafé Luisa, Veltman Joris A, Zabel Bernhard, Superti-Furga Andrea (2011), Chondrodysplasia and abnormal joint development associated with mutations in IMPAD1, encoding the Golgi-resident nucleotide phosphatase, gPAPP., in American journal of human genetics, 88(5), 608-15.
Circulating matrix γ-carboxyglutamate protein (MGP) species are refractory to vitamin K treatment in a new case of Keutel syndrome.
Cranenburg E C M, VAN Spaendonck-Zwarts K Y, Bonafe L, Mittaz Crettol L, Rödiger L A, Dikkers F G, VAN Essen A J, Superti-Furga A, Alexandrakis E, Vermeer C, Schurgers L J, Laverman G D (2011), Circulating matrix γ-carboxyglutamate protein (MGP) species are refractory to vitamin K treatment in a new case of Keutel syndrome., in Journal of thrombosis and haemostasis : JTH, 9(6), 1225-35.
Clinical and molecular characterization of Diastrophic Dysplasia in the Portuguese population.
Barbosa M, Sousa A B, Medeira A, Lourenço T, Saraiva J, Pinto-Basto J, Soares G, Fortuna A M, Superti-Furga A, Mittaz L, Reis-Lima M, Bonafé L (2011), Clinical and molecular characterization of Diastrophic Dysplasia in the Portuguese population., in Clinical genetics, 80(6), 550-7.
Genetic deficiency of tartrate-resistant acid phosphatase associated with skeletal dysplasia, cerebral calcifications and autoimmunity.
Lausch Ekkehart, Janecke Andreas, Bros Matthias, Trojandt Stefanie, Alanay Yasemin, De Laet Corinne, Hübner Christian A, Meinecke Peter, Nishimura Gen, Matsuo Mari, Hirano Yoshiko, Tenoutasse Sylvie, Kiss Andrea, Rosa Rafael Fabiano Machado, Unger Sharon L, Renella Raffaele, Bonafé Luisa, Spranger Jürgen, Unger Sheila, Zabel Bernhard, Superti-Furga Andrea (2011), Genetic deficiency of tartrate-resistant acid phosphatase associated with skeletal dysplasia, cerebral calcifications and autoimmunity., in Nature genetics, 43(2), 132-7.
Hyaline fibromatosis syndrome inducing mutations in the ectodomain of anthrax toxin receptor 2 can be rescued by proteasome inhibitors.
Deuquet Julie, Lausch Ekkehart, Guex Nicolas, Abrami Laurence, Salvi Suzanne, Lakkaraju Asvin, Ramirez Maria Celeste M, Martignetti John A, Rokicki Dariusz, Bonafe Luisa, Superti-Furga Andrea, van der Goot Françoise G (2011), Hyaline fibromatosis syndrome inducing mutations in the ectodomain of anthrax toxin receptor 2 can be rescued by proteasome inhibitors., in EMBO molecular medicine, 3(4), 208-21.
Recurrent dominant mutations affecting two adjacent residues in the motor domain of the monomeric kinesin KIF22 result in skeletal dysplasia and joint laxity.
Boyden Eric D, Campos-Xavier A Belinda, Kalamajski Sebastian, Cameron Trevor L, Suarez Philippe, Tanackovic Goranka, Tanackovich Goranka, Andria Generoso, Ballhausen Diana, Briggs Michael D, Hartley Claire, Cohn Daniel H, Davidson H Rosemarie, Hall Christine, Ikegawa Shiro, Jouk Pierre-Simon, König Rainer, Megarbané André, Nishimura Gen, Lachman Ralph S, Mortier Geert, Rimoin David L, Rogers R Curtis, Rossi Massimiliano, Sawada Hirotake (2011), Recurrent dominant mutations affecting two adjacent residues in the motor domain of the monomeric kinesin KIF22 result in skeletal dysplasia and joint laxity., in American journal of human genetics, 89(6), 767-72.
Loss-of-function mutations in PTPN11 cause metachondromatosis, but not Ollier disease or Maffucci syndrome
Bowen M. E., Boyden E. D., Holm I. A., Campos-Xavier B., Bonafe L., Superti-Furga A., Ikegawa S., Cormier-Daire V., Bovee J. V., Pansuriya T. C., de Sousa S. B., Savarirayan R., Andreucci E., Vikkula M., Garavelli L., Pottinger C., Ogino T., Sakai A., Regazzoni B. M., Wuyts W., Sangiorgi L., Pedrini E., Zhu M., Kozakewich H. P., Kasser J. R., Loss-of-function mutations in PTPN11 cause metachondromatosis, but not Ollier disease or Maffucci syndrome, in PLoS Genet, 7(4).
Pseudoachondroplasia and multiple epiphyseal dysplasia: A 7-year comprehensive analysis of the known disease genes identify novel and recurrent mutations and provides an accurate assessment of their relative contribution
Jackson G. C., Mittaz-Crettol L., Taylor J. A., Mortier G. R., Spranger J., Zabel B., Le Merrer M., Cormier-Daire V., Hall C. M., Offiah A., Wright M. J., Savarirayan R., Nishimura G., Ramsden S. C., Elles R., Bonafe L., Superti-Furga A., Unger S., Zankl A., Briggs M. D., Pseudoachondroplasia and multiple epiphyseal dysplasia: A 7-year comprehensive analysis of the known disease genes identify novel and recurrent mutations and provides an accurate assessment of their relative contribution, in Hum Mutat.
Whole-exome sequencing detects somatic mutations of IDH1 in metaphyseal chondromatosis with D-2-hydroxyglutaric aciduria (MC-HGA)
Vissers L. E., Fano V., Martinelli D., Campos-Xavier B., Barbuti D., Cho T. J., Dursun A., Kim O. H., Lee S. H., Timpani G., Nishimura G., Unger S., Sass J. O., Veltman J. A., Brunner H. G., Bonafe L., Dionisi-Vici C., Superti-Furga A., Whole-exome sequencing detects somatic mutations of IDH1 in metaphyseal chondromatosis with D-2-hydroxyglutaric aciduria (MC-HGA), in Am J Med Genet A, 155.

Collaboration

Group / person Country
Types of collaboration
Istituto di Biochimica Università Pavia Italy (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Exchange of personnel
Sunnybrook Health Sciences Centre, Toronto Canada (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Harvard University United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
International Skeletal Dysplasia Society (ISDS) Biannual meeting Talk given at a conference Putative gain of function mutations in FAM111A result in Kenny-Caffey syndrome and Osteocraniostenosis: identification of an upstream regulator of the PTH axis 29.08.2013 Bologna, Italy Suarez Philippe; Bonafé Luisa;
International Skeletal Dysplasia Society (ISDS) Biannual meeting Poster Homozygosity for a novel truncating mutation confirms TBX15 deficiency as the cause of Cousin Syndrome 29.08.2013 Bologna, Italy Suarez Philippe; Bonafé Luisa;
International Skeletal Dysplasia Society (ISDS) Biannual meeting Poster Losartan Treatment In Camurati-Engelmann Disease: An Experience In An Adolescent Patient 29.08.2013 Bologna, Italy Suarez Philippe; Bonafé Luisa;
International Skeletal Dysplasia Society (ISDS) Biannual meeting Talk given at a conference The Gpc6 knockout mouse model for recessive omodysplasia. 29.08.2013 Bologna, Italy Bonafé Luisa; Suarez Philippe;
International Skeletal Dysplasia Society (ISDS) Biannual meeting Talk given at a conference MMP13 mutations are the cause of recessive metaphyseal dysplasia, Spahr type 29.08.2013 Bologna, Italy Suarez Philippe; Bonafé Luisa;
International Congress of Human Genetics 2011 Poster Spondylothoracic dysostosis, spondylocostal dysostosis type 2, and the mutational spectrum of MESP2: protein modelling helps explain phenotypic differences from the genotype. 11.10.2011 Montreal, Canada Bonafé Luisa;
International Congress of Human Genetics 2011 Poster Expanding the phenotype of the novel Ehlers-Danlos caused by mutations in the CHST14 gene. 11.10.2011 Montreal, Canada, Canada Bonafé Luisa;
International Congress of Human Genetics 2011 Poster Chondrodysplasia, joint dislocations, brachydactyly and cleft palate caused by recessive mutations in IMPAD1, the gene coding for the Golgi-resident nucleotide phosphatase, gPAPP: a novel distinct phenotype associated with a proteoglycan sulfation defect. 11.10.2011 Montreal, Canada Bonafé Luisa;
International Skeletal Dysplasia Society (ISDS) Biannual meeting Talk given at a conference Cleft palate, chondrodysplasia and abnormal joint development associated with recessive mutations in IMPAD1, the gene coding for the Golgi-resident nucleotide phosphatase, gPAPP. 23.06.2011 Palm Cove, Australia, Australia Bonafé Luisa;
International Skeletal Dysplasia Society (ISDS) Biannual meeting Poster Spondylo-megaepiphyseal-metaphyseal dysplasia: severe neurologic manifestations from cervical spine instability. 23.06.2011 Palm Cove, Australia Bonafé Luisa;


Knowledge transfer events

Active participation

Title Type of contribution Date Place Persons involved
2nd Introductory Course of Skeletal Dysplasias 29.09.2014 Santos, Brazil Bonafé Luisa;
Special Course:Diagnosis and Management of Congenital Skeletal Malformations and Skeletal Dysplasias 01.10.2012 Campinas (Brazil), Brazil Bonafé Luisa;
Course "Hub and Spoke" on Skeletal Dysplasia 21.05.2012 Bologna (Italy), Italy Bonafé Luisa;


Self-organised

Title Date Place
8th Introductory Course on Skeletal dysplasias 07.07.2014 Lausanne, Switzerland
7th Introductory Course on Skeletal dysplasias 01.07.2013 Lausanne, Switzerland
6th Introductory Course on Skeletal Dysplasias 02.07.2012 Lausanne, Switzerland

Awards

Title Year
Clinical Research award 2011 of the Faculty of Biology and Medicine (University of Lausanne) 2011
The 2011 Maroteaux award (International Skeletal Dysplasia Society) 2011

Associated projects

Number Title Start Funding scheme
116506 Molecular basis of human skeletal dysplasias 01.04.2007 Project funding (Div. I-III)

Abstract

Skeletal dysplasias are genetic disorders of skeletal development and growth. They are characterized by severe short stature, deformity, and various complications such as chronic joint pain and disabilities in daily life. There is great phenotypic heterogeneity (more than 300 different genetic conditions) and only a limited part of the genes mutated in these conditions is known. The broader aim of our research is to gain information on the molecular mechanisms underlying skeletal dysplasias in humans.The present project follows a previous one, which focused on three skeletal disorders: autosomal recessive omodysplasia (ARO), SPONASTRIME dysplasia (SD), and spondylo-epi-metaphyseal dysplasia with joint laxity, leptodactylic type (Lepto-SEMDJL). ARO is a severe form of short-limbed dwarfism, whereas SD and Lepto-SEMDJL are spondylo-metaphyseal dysplasias with different degree of severity and joint involvement. We have studied these three disorders by a positional cloning approach. We have identified the gene responsible for ARO, the membrane-bound, glycosylphosphatidylinositol (GPI)-anchored, heparan-sulfate proteoglycan glypican 6 (GPC6). Glypicans function as co-receptors in the fine-tuning of cell signaling and morphogen gradients during development. Based on our previous results on specific growth plate differential expression of gpc6 and on the expansion of the proliferative zone in human ARO growth plate, we hypothesize that the loss of GPC6 impairs critical regulation of growth factors (i.e. FGF, IHH) particularly in proliferating chondrocytes with less efficient maturation into hypertrophic chondrocytes. In addition, recent data about the Piga mutant, a mouse model lacking all GPI-anchored proteins in the limb skeleton, point out the possible role of glypicans in defining chondrocyte cell polarity, essential for the architecture of the growth plate and for its role in bone elongation. To investigate the exact role of GPC6 in the growth plate and its mechanisms of action we plan to generate a gpc6 knockout mouse and to study the pathophysiology of the skeletal changes in this model.The other two disorders are presently characterized only at a phenotypic level; our previous work allowed the identification of genomic regions where the responsible genes are most likely located, however these regions are quite large and the responsible genes have not been identified yet. In this project we plan to refine the intervals of interest by including additional families that we could diagnose and recruit during the last years and resort to newer sequencing techniques (exon capturing and high-throughput sequencing) to identify the responsible genes.We expect the research results to be valuable at different levels. Gaining molecular information on genetic skeletal disorders will provide reliable diagnostic tests for genetic counseling, establish the biological basis for appropriate management of affected children and their families, and hopefully reveal some pathogenetic steps that might prove amenable to pharmacological therapy. The results shall shed light on the biological aspects of morphogenesis, development, growth, and homeostasis of the skeleton. Understanding the biology of bone and cartilage in rare disorders will provide insights on more common diseases, such as arthritis, osteoporosis and short stature.
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