Endocrine Gnetics

Pathophysiology and Therapy of Genetic Diseases
Hospital Universitario La Paz

Skeletal dysplasias (SD) encompass a complex group of 436 defined conditions affecting bone and cartilage growth. The underlying molecular defect remains unidentified in a relatively high proportion of patients, suggesting that further genes or mutations are implicated in both novel and already characterized signaling pathways.

During the last decade, we have also focused on the genetic and functional understanding of how SHOX (short stature homeobox-containing gene) is implicated in the skeletal development in two SD: Léri-Weill dyschondrosteosis (LWD) and Langer mesomelic dysplasia (LMD). We have identified downstream and upstream deletions, which were subsequently shown to include various SHOX regulatory sequences (enhancers), and the presence of SHOX duplications in these pathologies. We have also undertaken a candidate gene approach to investigate the presence of mutations in various genes in the Natriuretic peptide receptor B/guanylate cyclase B (NPR-B) pathway. We demonstrated that mutations in NPR2 which encodes NPR-B, account for ~3% of patients with disproportionate short stature and/or clinical or radiographic indicators of SHOX deficiency and in whom no SHOX defect has been identified. More recently, we have identified mutations in a novel gene in a related pathway in patients with disproportionate short stature.

We have extended our research interests into the molecular pathophysiology of all skeletal dysplasias, through the implementation of Next generation sequencing (NGS) technologies. We routinely use a targeted NGS panel, SKELETAL.SEQ to improve the detection of mutations and to aid our knowledge into the molecular basis of skeletal dysplasia. Mutations are identified in 53% of cases, with very rare cases being detected. We, subsequently, functionally characterize several of these mutations to determine the pathogenic mechanism. Exome sequencing is then undertaken in the negative cases with the aim to identify novel genes implicated in these disorders. 

The projects aims are to identify and functionally characterize novel genes and genomic regions implicated in the etiology of SD, using a combination of NGS technologies and functional assays.

Biomolecules & Cell D.
Molecular Biomedicine
Miriam Aza Carmona