Ignite Creation Date:
2024-05-05 @ 12:10 PM
Last Modification Date:
2024-10-26 @ 9:21 AM
Study NCT ID:
NCT00260897
Status:
UNKNOWN
Last Update Posted:
2007-05-08
First Post:
2005-12-01
Brief Title:
Molecular Genetic Study of Avascular Necrosis of the Femoral Head
Sponsor:
National Health Research Institutes Taiwan
Organization:
National Health Research Institutes Taiwan
Study Overview
Official Title:
Molecular Genetic Study of Avascular Necrosis of the Femoral Head-Revealing ANFH Pathogenesis Mechanism by Cell and Animal Models
Status:
UNKNOWN
Status Verified Date:
2007-05
Last Known Status:
RECRUITING
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Avascular necrosis of the femoral head ANFH is a debilitating disease that commonly leads to destruction of the hip joint in patients at middle age of life and often requires surgical intervention Previously we have identified the collagen type II alpha 1 COL2A1 gene as the ANFH disease gene In this grant proposal we will establish cell ine and animal models to understand the pathophysiology of ANFH and extend our ongoing study for identifying genes responsible for non-familiar ANFH by looking into other interacting molecules of the pathway
Detailed Description:
Avascular necrosis of the femoral head ANFH is a debilitating disease that usually leads to destruction of the hip joint in the third to fifth decade of life average age 36 years The disease prevalence is unknown but it has been estimated that 10000-20000 new cases per year are diagnosed in the United State Nearly half of the patients eventually require hip replacement before 40 years of age The etiology of ANFH is unknown but previous studies indicated that heritable thrombophilia increased tendency to form thrombi and hypofibrinolysis reduced ability to lyse thrombi alcohol intake and steroid use are risk factors for ANFH
Although the majority of idiopathic ANFH cases are sporadic recently we identified three ANFH families showing autosomal dominant inheritance By genome-wide scan a significant two-point LOD score of 345 at 0 was obtained between one ANFH pedigree and marker D12S85 on chromosome 12 High-resolution mapping was conducted in a second ANFH family and replicated the linkage to D12S368 When an age-dependent penetrance model was applied the combined multipoint LOD score achieved 643 between D12S1663 and D12S85 Furthermore by using haplotype analysis and gene-based mutation detection we have identified the collagen type II alpha 1 COL2A1 gene as the ANFH disease gene Re-sequencing of the type II collagen COL2A1 gene demonstrated a glycine with serine mutation in the G-X-Y repeat of type II collagen in all affected individuals in three pedigrees In the Pedigree I a 3665G A mutation in exon 50 of the COL2A1 gene Genbank accession number NM_001844 and the substitution resulted in a Gly1170Ser codon change Genbank accession number NP_001835 A second pedigree was shown to harbor the same mutation but the mutant allele existed in a different haplotype background In a third pedigree a 2306GA mutation occurred in exon 33 of the gene Genbank accession number NM_001844 causing glycine to serine change at codon 717 Genbank accession number NP_001835
On this basis we propose to study the pathophysiological mechanisms of inherited and sporadic ANFH The main focus of this project includes 1 Establishing cell line and animal models to investigate the molecular basis of ANFH pathogenesis 2 Conducting genetic analysis on sporadic ANFH cases including those who are idiopathic alcohol consumers or steroid-induced 3 Using COL2A1 gene as a target we will design novel therapeutics and prediction procedures to improve the management of the ANFH patients
Although the majority of idiopathic ANFH cases are sporadic recently we identified three ANFH families showing autosomal dominant inheritance By genome-wide scan a significant two-point LOD score of 345 at 0 was obtained between one ANFH pedigree and marker D12S85 on chromosome 12 High-resolution mapping was conducted in a second ANFH family and replicated the linkage to D12S368 When an age-dependent penetrance model was applied the combined multipoint LOD score achieved 643 between D12S1663 and D12S85 Furthermore by using haplotype analysis and gene-based mutation detection we have identified the collagen type II alpha 1 COL2A1 gene as the ANFH disease gene Re-sequencing of the type II collagen COL2A1 gene demonstrated a glycine with serine mutation in the G-X-Y repeat of type II collagen in all affected individuals in three pedigrees In the Pedigree I a 3665G A mutation in exon 50 of the COL2A1 gene Genbank accession number NM_001844 and the substitution resulted in a Gly1170Ser codon change Genbank accession number NP_001835 A second pedigree was shown to harbor the same mutation but the mutant allele existed in a different haplotype background In a third pedigree a 2306GA mutation occurred in exon 33 of the gene Genbank accession number NM_001844 causing glycine to serine change at codon 717 Genbank accession number NP_001835
On this basis we propose to study the pathophysiological mechanisms of inherited and sporadic ANFH The main focus of this project includes 1 Establishing cell line and animal models to investigate the molecular basis of ANFH pathogenesis 2 Conducting genetic analysis on sporadic ANFH cases including those who are idiopathic alcohol consumers or steroid-induced 3 Using COL2A1 gene as a target we will design novel therapeutics and prediction procedures to improve the management of the ANFH patients
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None