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Bone Abstracts (2016) 5 P244 | DOI: 10.1530/boneabs.5.P244

1University of Milan, Milan, Italy; 2Humanitas Clinical and Research Institute, Rozzano, Milan, Italy; 3University of Turin, Turin, Italy; 4CNR-IRGB, Milan Unit, Milan, Italy; 5CRS4, Pula, Cagliari, Italy; 6San Raffaele TIGET, Milan, Italy; 7University of Perugia, Perugia, Italy.

Acrofrontofacionasal Dysostosis type 1 (AFFND1) is a rare human syndrome (estimated prevalence lower than 1:1,000,000), characterized by bone abnormalities in addition to other multiple congenital anomalies and intellectual disability. Only four AFFND1 families, three of Brazilian and one of Indian origin, have been described so far and an autosomal recessive pattern of inheritance has been suggested. The patients are severely affected: the main clinical features are intellectual disability, short stature, facial and skeletal abnormalities characterized by cleft lip/palate, campto-brachy-poly-syndactyly and marked anomalies of foot structures.

Exome sequencing in the Indian family, comprising two affected siblings and their parents identified a putative candidate variant in an intronic region of the Neuroblastoma Amplified Sequence (NBAS) gene. This variant was confirmed by Sanger sequencing in the patients and their parents. Since it was located close to an acceptor splice site and predicted to impact on the splicing process, its effect was verified on the cDNA of the patients, and indeed this genomic change was found to cause skipping of exon 48 and premature termination of transcription. Evaluation of expression of the NBAS gene in the mouse osteoblast lineage by semiquantitative RT-PCR showed that NBAS expression was almost completely absent in undifferentiated murine Mesenchymal Stem Cells (mMSCs), but greatly increased in mature osteoblasts derived from them. In addition, immunohistochemical analysis of NBAS during murine fetal life starting at embryonic day (E) 11.5 (that is, when skeletal elements begin to form) showed a pattern of expression in agreement with the multiple abnormalities presented by AFFND1 patients in keeping with its possible role in developmental processes.

Further investigations are ongoing in order to unravel the role of the NBAS gene in the pathogenesis of AFFND1 and in general in developmental pathophysiology.

Volume 5

43rd Annual European Calcified Tissue Society Congress

Rome, Italy
14 May 2016 - 17 May 2016

European Calcified Tissue Society 

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