复旦大学：《医学遗传学 Medical Genetics》课程教学资源（学习报告）Fibrodysplasia ossificans Progressvia

Fibrodysplasia ossificans Progressiva(FOP) Samantha he Medical Genetics 12/31/09

Fibrodysplasia ossificans Progressiva (FOP) Samantha He Medical Genetics 12/31/09

A baffling and rare disease John Ferke of Saint Bartholomews Hospital, 1741 They arise from all over the vertebrae of the neck and reach down to the sacrum they likewise arise from every rib of his body and joining together in all parts of his back, as the ramifications of corals do, they make as it were a fixed bony pair of bodice

A baffling and rare disease John Ferke of Saint Bartholomew’s Hospital, 1741: ‘ …They arise from all over the vertebrae of the neck and reach down to the sacrum; they likewise arise from every rib of his body, and joining together in all parts of his back, as the ramifications of corals do, they make as it were, a fixed bony pair of bodice.’

General overview of fop Soft connective tissue that progressively turn into bone Occurrence: 1 2,000,000 Regardless of gender and ethnicity zoo confirmed cases in the world, 285 known cases in U.S Misdiagnosis rate around 60%80% Cancer Juvenile fibromatosis Median age of survival: 45 years ° Nocure

General overview of FOP • Soft connective tissue that progressively turn into bone • Occurrence: 1 /2,000,000 ▫ Regardless of gender and ethnicity • 700 confirmed cases in the world, 285 known cases in U.S • Misdiagnosis rate around 60%~80% ▫ Cancer ▫ Juvenile Firbromatosis • Median age of survival: 45 years • No cure

a (Kaplan et al. 2008)

(Kaplan et al. 2008)

Genetics of fop Discovered in 2006 Heritable in typical autosomal dominant pattern Low reproductive fitness Complete penetrance Phenotype: Heterotopic OssificanS (HO) Heterotopic= misplaced Heterozygous point mutation on Activin Receptor IA (ACVR1) gene Novel mutations cause atypical FOP

Genetics of FOP • Discovered in 2006 • Heritable in typical autosomal dominant pattern • Low reproductive fitness • Complete penetrance • Phenotype: Heterotopic Ossificans (HO) ▫ Heterotopic = misplaced • Heterozygous point mutation on Activin Receptor IA (ACVR1) gene ▫ Novel mutations cause atypical FOP

Cytogenic Location °2q23-q24 (ACVR1, n.d., Where is ACVR1 located, figure 1) C LILT LILIL W IIIILII II IIID |公 AN

Cytogenic Location (“ACVR1,” n.d., Where is ACVR1 located, figure 1) • 2q23-q24

F0:2 FOP 00H 00^,0 121234 (Feldman et al. 2000)

(Feldman et al. 2000)

ACVR1 Also known as Activin receptor-like kinase-2(ALK2) Gene Codes for Activin receptor type 1 protein ACVRI protein function Controls and regulates growth of bones, muscles and ossification recruit and phosphorylate signaling molecules (Smad) Signaled by bone morphogenic protein(BMP) Effects growth and differentiation of cells Mutation Ligand dependent over responsiveness Ligand independent leakiness

ACVR1 • Also known as Activin receptor-like kinase-2 (ALK2) • Gene ▫ Codes for Activin receptor type 1 protein • ACVR1 protein function ▫ Controls and regulates growth of bones, muscles and ossification recruit and phosphorylate signaling molecules (Smad) ▫ Signaled by bone morphogenic protein (BMP) ▫ Effects growth and differentiation of cells • Mutation: ▫ Ligand dependent over responsiveness ▫ Ligand independent leakiness

How AVCR1 works ONTROL SM-FKBP12 cvR1 SM-FKBP12………ACVR1(R206H ⊥ BMP Basally Leaky Signaling BMP Signaling Blocked in Absence of Ligand ACVR1 ACVR1(R206H) ↓↓↓ BMP per-responsive BMP Signaling (Kaplan et al. 2008) in Presence of Ligand

How AVCR1 works (Kaplan et al. 2008)

AVCR1 schematic diagram Typical mutation on AVCRl Missense mutation at codon 206 of gs region 107124146178208 I Ligand-bindingTM GS Protein kinase domain 509aa W… GTG GCT CGC CAG ATT… - Val-Ala-Arg-GIn-lle GTG GCT CAC CAG ATT FOP Va-Aa-Hs·Gn-|le Codon:204205206207208 (Shore et al. 2008)

AVCR1 schematic diagram • Typical mutation on AVCR1 • Missense mutation at codon 206 of GS region (Shore et al. 2008)