The rockefeller university

Event Details

Type

Special Seminar Series

Speaker(s)

Valerie Cormier-Daire, M.D., Ph.D., professor of genetics, Paris Descartes University; team leader, INSERM and Fondation Imagine

Speaker bio(s)

The acromelic dysplasia group includes four disorders namely Weill-Marchesani Syndrome (WMS), Geleophysic Dysplasia (GD), Acromicric dysplasia (AD) and Myhre syndrome (MS), all characterized by severe short stature, short extremities, restricted joint mobility, thick skin and pseudomuscular build. They are distinct by additional features and their pattern inheritance. WMS is characterized by the presence of dislocation of microspherophakia and has autosomal dominant or recessive mode of inheritance. GD is the more severe one, characterized by a progressive cardiac valvular thickening, often leading to an early death. AD has an autosomal dominant mode of inheritance. Finally, MS is characterized by prognathism, deafness and developmental delay.

Dr. Cormier-Daire and her colleagues first identified mutations in Fibrillin1 (FBN1) in the dominant form of WMS and then mutations in A Disintegrin-like and Metalloproteinase domain with ThromboSpondin type 1 repeats 10 (ADAMTS10) in the recessive form of WMS.

They then identified mutations in ADAMTSL2 in the recessive form of GD and a hotspot of mutations in FBN1 in the dominant form of GD and in AD exon 41-42, encoding TGFβ binding protein-like domain 5 (TB5) of FBN1. Using a yeast double hybrid screen, the group identified Latent TGFβ Binding Protein 1 as a partner of ADAMTSL2. They found an increased level of active TGFβ in the fibroblast medium from patients with FBN1 or ADAMTSL2 mutations and an enhanced phoshorylated SMAD2 level, allowing them to conclude at an enhanced TGFβ signaling in GD and AD. Finally, a direct interaction between ADAMTSL2 and FBN1 was demonstrated, suggesting a dysregulation of FBN1/ADAMTSL2/TGFβ interrelationship as the underlying mechanism of the short stature phenotypes.

To identify the gene responsible for MS, Dr. Cormier-Daire and her colleagues performed exome sequencing in 2 MS. They identified de novo missense mutations, all involving Isoleucine residue at position 500, in the MH2 domain of SMAD4 in a total of 20 MS patients. In MS fibroblasts, they found decreased ubiquitination level of SMAD4 and increased level of SMAD4, supporting a stabilization of SMAD4 protein. Functional SMAD4 is required for canonical signal transduction through the oligomerization with phosphorylated SMAD2/3 and SMAD1/5/8. The group therefore studied the nuclear localization of mutant SMAD complexes and found that the complexes translocate to the nucleus. Finally, they observed a decreased expression of downstream TGFβ target genes supporting impaired TGFβ driven transcriptional control in MS.

All together, these findings support a direct link between the short stature phenotypes and the TGFβ signalling. However, the finding of enhanced TGFβ signaling in Marfan phenotypes suggests the existence of yet unknown mechanisms regulating this pathway, possibly including tissue specific  modulations. Finally, remembering the severity of GD, Dr. Cormier-Daire's ultimate goal is the design of drugs that can selectively inhibit this pathway.

Dr. Cormier-Daire completed her residency in pediatrics from 1986 to 1992, and received her Ph.D. from University of Paris VI in 1993. She was then a fellow in medical genetics at Necker Hospital for Sick Children in Paris from 1993 to 1996 and completed a postdoctoral fellowship at Cedars Sinai Medical center in Los Angeles from 1998 to 1999, working with the international registry for skeletal dysplasia. Dr. Cormier-Daire held a tenure medical position in the department of medical genetics at Necker Hospital from 1997 to 2005. She is presently a professor of genetics at Paris Descartes University and a leader of the "molecular and physiopathological bases of osteochondrodysplasia" project at INSERM. This year, Dr. Cormier-Daire became head of the French reference center for skeletal dysplasia dedicated to the diagnosis and long term follow-up of patients with osteochondrodypslasia. She is a member of the American Society of Human Genetics, the European Society of Human Genetics, the council of the International Skeletal Dysplasia Society, the European Skeletal Dysplasia Network, and has been vice president of the French Association of Clinical Genetics-Genetic Counseling since 2011.

Open to

Public

Host

Jean-Laurent Casanova

Reception

Refreshments, 3:45 p.m. - 4:00 p.m., Lower Level Greenberg Building (CRC)

Contact

Jill Benz

Phone

(212) 327-7244

Sponsor

Jill Benz
(212) 327-7244
benzj@rockefeller.edu