title: Mutations in the TGFβ binding-protein-like domain 5 of FBN1 are responsible for acromicric and geleophysic dysplasias.
abstract: Geleophysic (GD) and acromicric dysplasia (AD) belong to the acromelic dysplasia group and are both characterized by severe short stature, short extremities, and stiff joints. Although AD has an unknown molecular basis, we have previously identified ADAMTSL2 mutations in a subset of GD patients. After exome sequencing in GD and AD cases, we selected fibrillin 1 (FBN1) as a candidate gene, even though mutations in this gene have been described in Marfan syndrome, which is characterized by tall stature and arachnodactyly. We identified 16 heterozygous FBN1 mutations that are all located in exons 41 and 42 and encode TGFβ-binding protein-like domain 5 (TB5) of FBN1 in 29 GD and AD cases. Microfibrillar network disorganization and enhanced TGFβ signaling were consistent features in GD and AD fibroblasts. Importantly, a direct interaction between ADAMTSL2 and FBN1 was demonstrated, suggesting a disruption of this interaction as the underlying mechanism of GD and AD phenotypes. Although enhanced TGFβ signaling caused by FBN1 mutations can trigger either Marfan syndrome or GD and AD, our findings support the fact that TB5 mutations in FBN1 are responsible for short stature phenotypes.
authors.affiliation: Department of Genetics, Université Paris Descartes, Unité Institut National de la Santé et de la Recherche Médicale, Hôpital Necker Enfants Malades, Paris, France.
authors.forename: Carine
authors.initials: C
authors.lastname: Le Goff
authors.forename: Clémentine
authors.initials: C
authors.lastname: Mahaut
authors.forename: Lauren W
authors.initials: LW
authors.lastname: Wang
authors.forename: Slimane
authors.initials: S
authors.lastname: Allali
authors.forename: Avinash
authors.initials: A
authors.lastname: Abhyankar
authors.forename: Sacha
authors.initials: S
authors.lastname: Jensen
authors.forename: Louise
authors.initials: L
authors.lastname: Zylberberg
authors.forename: Gwenaelle
authors.initials: G
authors.lastname: Collod-Beroud
authors.forename: Damien
authors.initials: D
authors.lastname: Bonnet
authors.forename: Yasemin
authors.initials: Y
authors.lastname: Alanay
authors.forename: Angela F
authors.initials: AF
authors.lastname: Brady
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Cordier
authors.forename: Koen
authors.initials: K
authors.lastname: Devriendt
authors.forename: David
authors.initials: D
authors.lastname: Genevieve
authors.forename: Pelin Özlem Simsek
authors.initials: PÖ
authors.lastname: Kiper
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kitoh
authors.forename: Deborah
authors.initials: D
authors.lastname: Krakow
authors.forename: Sally Ann
authors.initials: SA
authors.lastname: Lynch
authors.forename: Martine
authors.initials: M
authors.lastname: Le Merrer
authors.forename: André
authors.initials: A
authors.lastname: Mégarbane
authors.forename: Geert
authors.initials: G
authors.lastname: Mortier
authors.forename: Sylvie
authors.initials: S
authors.lastname: Odent
authors.forename: Michel
authors.initials: M
authors.lastname: Polak
authors.forename: Marianne
authors.initials: M
authors.lastname: Rohrbach
authors.forename: David
authors.initials: D
authors.lastname: Sillence
authors.forename: Irene
authors.initials: I
authors.lastname: Stolte-Dijkstra
authors.forename: Andrea
authors.initials: A
authors.lastname: Superti-Furga
authors.forename: David L
authors.initials: DL
authors.lastname: Rimoin
authors.forename: Vicken
authors.initials: V
authors.lastname: Topouchian
authors.forename: Sheila
authors.initials: S
authors.lastname: Unger
authors.forename: Bernhard
authors.initials: B
authors.lastname: Zabel
authors.forename: Christine
authors.initials: C
authors.lastname: Bole-Feysot
authors.forename: Patrick
authors.initials: P
authors.lastname: Nitschke
authors.forename: Penny
authors.initials: P
authors.lastname: Handford
authors.forename: Jean-Laurent
authors.initials: JL
authors.lastname: Casanova
authors.forename: Catherine
authors.initials: C
authors.lastname: Boileau
authors.forename: Suneel S
authors.initials: SS
authors.lastname: Apte
authors.forename: Arnold
authors.initials: A
authors.lastname: Munnich
authors.forename: Valérie
authors.initials: V
authors.lastname: Cormier-Daire
mesh_terms: D000293:Adolescent; D000328:Adult; D001848:Bone Diseases, Developmental / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D003238:Connective Tissue / Q000002:abnormalities; D004252:DNA Mutational Analysis; D004392:Dwarfism / Q000235:genetics*; D005091:Exons; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005124:Eye Abnormalities / Q000235:genetics*; D000071838:Fibrillin-1; D000071837:Fibrillins; D005455:Fluorescent Antibody Technique; D006579:Heterozygote; D006801:Humans; D002479:Inclusion Bodies / Q000235:genetics; D017880:Limb Deformities, Congenital / Q000235:genetics*; D008382:Marfan Syndrome / Q000235:genetics; D020894:Microfibrils / Q000648:ultrastructure; D008840:Microfilament Proteins / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D055815:Young Adult; D054392:Adipokines
chemical_list: D016326:Extracellular Matrix Proteins; D000071838:Fibrillin-1; D000071837:Fibrillins; D008840:Microfilament Proteins; D053773:Transforming Growth Factor beta1; C000605722:FBN1 protein, human; D054392:Adipokines