Leri's pleonosteosis, a congenital rheumatic disease, results from microduplication at 8q22.1 encompassing GDF6 and SDC2 and provides insight into systemic sclerosis pathogenesis.
OBJECTIVE
Leri's pleonosteosis (LP) is an autosomal dominant rheumatic condition characterised by flexion contractures of the interphalangeal joints, limited motion of multiple joints, and short broad metacarpals, metatarsals and phalanges. Scleroderma-like skin thickening can be seen in some individuals with LP. We undertook a study to characterise the phenotype of LP and identify its genetic basis.


RESULTS
Whole-genome single-nucleotide polymorphism genotyping in two families with LP defined microduplications of chromosome 8q22.1 as the cause of this condition. Expression analysis of dermal fibroblasts from affected individuals showed overexpression of two genes, GDF6 and SDC2, within the duplicated region, leading to dysregulation of genes that encode proteins of the extracellular matrix and downstream players in the transforming growth factor (TGF)-β pathway. Western blot analysis revealed markedly decreased inhibitory SMAD6 levels in patients with LP. Furthermore, in a cohort of 330 systemic sclerosis cases, we show that the minor allele of a missense SDC2 variant, p.Ser71Thr, could confer protection against disease (p<1×10(-5)).


CONCLUSIONS
Our work identifies the genetic cause of LP in these two families, demonstrates the phenotypic range of the condition, implicates dysregulation of extracellular matrix homoeostasis genes in its pathogenesis, and highlights the link between TGF-β/SMAD signalling, growth/differentiation factor 6 and syndecan-2. We propose that LP is an additional member of the growing 'TGF-β-pathies' group of musculoskeletal disorders, which includes Myhre syndrome, acromicric dysplasia, geleophysic dysplasias, Weill-Marchesani syndromes and stiff skin syndrome. Identification of a systemic sclerosis-protective SDC2 variant lays the foundation for exploration of the role of syndecan-2 in systemic sclerosis in the future.
Faculty of Medical and Human Sciences, Manchester Centre for Genomic Medicine, Institute of Human Development, University of Manchester, Manchester Academic Health Science Centre (MAHSC), Manchester, UK Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, MAHSC, Manchester, UK.
Siddharth
http://orcid.org/0000-0002-8527-2210
S
Banka
Faculty of Life Sciences, Wellcome Trust Centre for Cell-Matrix Research, University of Manchester, Manchester, UK.
Stuart A
SA
Cain
Faculty of Medical and Human Sciences, Manchester Centre for Genomic Medicine, Institute of Human Development, University of Manchester, Manchester Academic Health Science Centre (MAHSC), Manchester, UK.
Sabrya
S
Carim
Faculty of Medical and Human Sciences, Manchester Centre for Genomic Medicine, Institute of Human Development, University of Manchester, Manchester Academic Health Science Centre (MAHSC), Manchester, UK.
Sarah B
SB
Daly
Faculty of Medical and Human Sciences, Manchester Centre for Genomic Medicine, Institute of Human Development, University of Manchester, Manchester Academic Health Science Centre (MAHSC), Manchester, UK.
Jill E
JE
Urquhart
Faculty of Medical and Human Sciences, Manchester Centre for Genomic Medicine, Institute of Human Development, University of Manchester, Manchester Academic Health Science Centre (MAHSC), Manchester, UK Department of Environmental Health and Biosafety, Health College, Çanakkale Onsekiz Mart University, Çanakkale, Turkey.
Günhan
G
Erdem
Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, MAHSC, Manchester, UK.
Jade
J
Harris
Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, MAHSC, Manchester, UK.
Michelle
M
Bottomley
Faculty of Medical and Human Sciences, Manchester Centre for Genomic Medicine, Institute of Human Development, University of Manchester, Manchester Academic Health Science Centre (MAHSC), Manchester, UK Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, MAHSC, Manchester, UK.
Dian
D
Donnai
Faculty of Medical and Human Sciences, Manchester Centre for Genomic Medicine, Institute of Human Development, University of Manchester, Manchester Academic Health Science Centre (MAHSC), Manchester, UK Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, MAHSC, Manchester, UK.
Bronwyn
B
Kerr
Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, MAHSC, Manchester, UK.
Helen
H
Kingston
Department of Pediatrics, University of Lausanne, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
Andreas
A
Superti-Furga
Department of Genetics, University of Lausanne, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
Sheila
S
Unger
Arthritis Research UK Epidemiology Unit, Centre for Musculoskeletal Research, University of Manchester, MAHSC, Manchester, UK.
Holly
H
Ennis
Arthritis Research UK Epidemiology Unit, Centre for Musculoskeletal Research, University of Manchester, MAHSC, Manchester, UK NIHR Manchester Musculoskeletal Biomedical Research Unit, Manchester Academy of Health Sciences, Manchester, UK.
Jane
J
Worthington
NIHR Manchester Musculoskeletal Biomedical Research Unit, Manchester Academy of Health Sciences, Manchester, UK.
Ariane L
AL
Herrick
Stem Cell Glycobiology Group, School of Materials, University of Manchester, Manchester, UK.
Catherine L R
CL
Merry
Structural Genomics Consortium, University of Oxford, Oxford, UK.
Wyatt W
WW
Yue
Faculty of Life Sciences, Wellcome Trust Centre for Cell-Matrix Research, University of Manchester, Manchester, UK.
Cay M
CM
Kielty
Faculty of Medical and Human Sciences, Manchester Centre for Genomic Medicine, Institute of Human Development, University of Manchester, Manchester Academic Health Science Centre (MAHSC), Manchester, UK Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, MAHSC, Manchester, UK.
William G
WG
Newman
D000328:Adult; D000368:Aged; D002675:Child, Preschool; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics*; D005109:Extracellular Matrix / Q000378:metabolism; D019066:Facies; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D020440:Gene Duplication; D020869:Gene Expression Profiling; D055431:Growth Differentiation Factor 6 / Q000235:genetics* / Q000378:metabolism; D006228:Hand Deformities, Congenital / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D007223:Infant; D007592:Joint Diseases / Q000151:congenital* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D009999:Ossification, Heterotopic / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D010641:Phenotype; D012595:Scleroderma, Systemic / Q000235:genetics*; D015398:Signal Transduction; D053669:Syndecan-2 / Q000235:genetics* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D055815:Young Adult
C525906:GDF6 protein, human; D055431:Growth Differentiation Factor 6; C508245:SDC2 protein, human; D016212:Transforming Growth Factor beta; D053669:Syndecan-2
Arthritis; Gene Polymorphism; Systemic Sclerosis