Tags

Type your tag names separated by a space and hit enter

Mutational analysis of the ACVR1 gene in Italian patients affected with fibrodysplasia ossificans progressiva: confirmations and advancements.
Eur J Hum Genet. 2009 Mar; 17(3):311-8.EJ

Abstract

Fibrodysplasia ossificans progressiva (FOP, MIM 135100) is a rare genetic disorder characterized by congenital great toe malformations and progressive heterotopic ossification transforming skeletal muscles and connective tissues to bone following a well-defined anatomic pattern of progression. Recently, FOP has been associated with a specific mutation of ACVR1, the gene coding for a bone morphogenetic protein type I receptor. The identification of ACVR1 as the causative gene for FOP now allows the genetic screening of FOP patients to identify the frequency of the identified recurrent ACVR1 mutation and to investigate genetic variability that may be associated with this severely debilitating disease. We report the screening for mutations in the ACVR1 gene carried out in a cohort of 17 Italian patients. Fifteen of these displayed the previously described c.617G>A mutation, leading to the R206H substitution in the GS domain of the ACVR1 receptor. In two patients, we found a novel mutation c.774G>C, leading to the R258S substitution in the kinase domain of the ACVR1 receptor. In the three-dimensional model of protein structure, R258 maps in close proximity to the GS domain, a key regulator of ACVR1 activity, where R206 is located. The GS domain is known to bind the regulatory protein FKBP12 and to undergo multiple phosphorylation events that trigger a signaling cascade inside the cell. The novel amino-acid substitution is predicted to influence either the conformation/stability of the GS region or the binding affinity with FKBP12, resulting in a less stringent inhibitory control on the ACVR1 kinase activity.

Authors+Show Affiliations

Laboratory of Molecular Genetics, G Gaslini Institute, Genova, Italy.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18830232

Citation

Bocciardi, Renata, et al. "Mutational Analysis of the ACVR1 Gene in Italian Patients Affected With Fibrodysplasia Ossificans Progressiva: Confirmations and Advancements." European Journal of Human Genetics : EJHG, vol. 17, no. 3, 2009, pp. 311-8.
Bocciardi R, Bordo D, Di Duca M, et al. Mutational analysis of the ACVR1 gene in Italian patients affected with fibrodysplasia ossificans progressiva: confirmations and advancements. Eur J Hum Genet. 2009;17(3):311-8.
Bocciardi, R., Bordo, D., Di Duca, M., Di Rocco, M., & Ravazzolo, R. (2009). Mutational analysis of the ACVR1 gene in Italian patients affected with fibrodysplasia ossificans progressiva: confirmations and advancements. European Journal of Human Genetics : EJHG, 17(3), 311-8. https://doi.org/10.1038/ejhg.2008.178
Bocciardi R, et al. Mutational Analysis of the ACVR1 Gene in Italian Patients Affected With Fibrodysplasia Ossificans Progressiva: Confirmations and Advancements. Eur J Hum Genet. 2009;17(3):311-8. PubMed PMID: 18830232.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Mutational analysis of the ACVR1 gene in Italian patients affected with fibrodysplasia ossificans progressiva: confirmations and advancements. AU - Bocciardi,Renata, AU - Bordo,Domenico, AU - Di Duca,Marco, AU - Di Rocco,Maja, AU - Ravazzolo,Roberto, Y1 - 2008/10/01/ PY - 2008/10/3/pubmed PY - 2009/4/25/medline PY - 2008/10/3/entrez SP - 311 EP - 8 JF - European journal of human genetics : EJHG JO - Eur J Hum Genet VL - 17 IS - 3 N2 - Fibrodysplasia ossificans progressiva (FOP, MIM 135100) is a rare genetic disorder characterized by congenital great toe malformations and progressive heterotopic ossification transforming skeletal muscles and connective tissues to bone following a well-defined anatomic pattern of progression. Recently, FOP has been associated with a specific mutation of ACVR1, the gene coding for a bone morphogenetic protein type I receptor. The identification of ACVR1 as the causative gene for FOP now allows the genetic screening of FOP patients to identify the frequency of the identified recurrent ACVR1 mutation and to investigate genetic variability that may be associated with this severely debilitating disease. We report the screening for mutations in the ACVR1 gene carried out in a cohort of 17 Italian patients. Fifteen of these displayed the previously described c.617G>A mutation, leading to the R206H substitution in the GS domain of the ACVR1 receptor. In two patients, we found a novel mutation c.774G>C, leading to the R258S substitution in the kinase domain of the ACVR1 receptor. In the three-dimensional model of protein structure, R258 maps in close proximity to the GS domain, a key regulator of ACVR1 activity, where R206 is located. The GS domain is known to bind the regulatory protein FKBP12 and to undergo multiple phosphorylation events that trigger a signaling cascade inside the cell. The novel amino-acid substitution is predicted to influence either the conformation/stability of the GS region or the binding affinity with FKBP12, resulting in a less stringent inhibitory control on the ACVR1 kinase activity. SN - 1476-5438 UR - https://www.unboundmedicine.com/medline/citation/18830232/Mutational_analysis_of_the_ACVR1_gene_in_Italian_patients_affected_with_fibrodysplasia_ossificans_progressiva:_confirmations_and_advancements_ L2 - https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/18830232/ DB - PRIME DP - Unbound Medicine ER -