Abstract
The human SHOX gene is composed of seven exons and encodes a paired-related homeodomain transcription factor. SHOX mutations or deletions have been associated with different short stature syndromes implying a role in growth and bone formation. During development, SHOX is expressed in a highly specific spatiotemporal expression pattern, the underlying regulatory mechanisms of which remain largely unknown. We have analysed SHOX expression in diverse embryonic, fetal and adult human tissues and detected expression in many tissues that were not known to express SHOX before, e.g. distinct brain regions. By using RT-PCR and comparing the results with RNA-Seq data, we have identified four novel exons (exon 2a, 7-1, 7-2 and 7-3) contributing to different SHOX isoforms, and also established an expression profile for the emerging new SHOX isoforms. Interestingly, we found the exon 7 variants to be exclusively expressed in fetal neural tissues, which could argue for a specific role of these variants during brain development. A bioinformatical analysis of the three novel 3′UTR exons yielded insights into the putative role of the different 3′UTRs as targets for miRNA binding. Functional analysis revealed that inclusion of exon 2a leads to nonsense-mediated RNA decay altering SHOX expression in a tissue and time specific manner. In conclusion, SHOX expression is regulated by different mechanisms and alternative splicing coupled with nonsense-mediated RNA decay constitutes a further component that can be used to fine tune the SHOX expression level.
Highlights
The human SHOX gene resides in the pseudoautosomal region 1 on the short arm of the X and Y chromosome
Besides the known SHOX expression in tissues involved in body growth such as chondrocytes and cartilage, SHOX is expressed in various other additional tissues, e.g. in different fetal and adult brain regions such as hindbrain, thalamus and basal ganglia, pointing to an additional function of SHOX during fetal brain development and maintenance of brain functions
Obvious brain malformations or cognitive developmental delay have not been described in patients with Leri-Weill Dyschondrosteosis (LWD), Turner or Langer syndrome or Idiopathic Short Stature (ISS) patients with SHOX haploinsufficiency
Summary
The human SHOX gene resides in the pseudoautosomal region 1 on the short arm of the X and Y chromosome. Homeodomain transcription factors are involved in the regulation of pattern formation, differentiation and organogenesis [2], and deficiencies in these genes can lead to a misregulation of developmental processes resulting in malformations [3,4]. SHOX defects are a major cause of Idiopathic Short Stature (ISS) and are involved in the etiopathology of Turner Syndrome [7,8]. In these syndromes, SHOX defects are implicated in inaccurate bone development and longitudinal body growth. Studies in human and chicken revealed specific SHOX expression in the pharyngeal arches and the early developing limbs during embryonic and fetal development, consistent with the symptoms seen in Turner and Langer syndrome as well as LWD [7,9]
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