Association of the Tag SNPs in the Human SKT Gene (KIAA1217) With Lumbar Disc Herniation

Abstract

Lumbar disc herniation (LDH) is one of the most common musculo-skeletal diseases. Recent studies have indicated that LDH has strong genetic determinants, and several susceptibility genes have been reported to associate with LDH; however, its etiology and pathogenesis still remain unclear. KIAA1217 (alias SKT, the human homolog of murine Skt [Sickle tail]) is a good candidate for an LDH susceptibility gene because SKT is specifically expressed in nucleus pulposa of intervertebral discs (IVDs) in humans and mice, and Skt Gt mice, which are established through a large-scale gene-trap mutagenesis, exhibit progressive, postnatal onset abnormality of the IVDs. Here, we report the association of SKT with LDH. Using tag SNPs, we examined the association in two independent Japanese case-control populations and found a significant association with SKT rs16924573 in the allele frequency model (p = 0.0015). The association was replicated in a Finnish case-control population (p = 0.026). The combined p value of the two population by meta-analysis is 0.00040 (OR, 1.34; 95% CI, 1.14-1.58). Our data indicate that SKT is involved in the etiology of LDH.

Integrin signalling adaptors: not only figurants in the cancer story

“…p140CAP has been shown to down-regulate integrin and growth factordependent signalling 39,40 . p140CAP 41,42 and SKT 43,44 are multisite docking proteins, characterized by conserved sequence motifs that can associate with multiple effectors (Figure 1). p140CAP is mainly expressed in brain, testes and epithelial-rich tissues such as mammary glands, lungs, colon and kidneys 41,45,46 and is phosphorylated on serine and tyrosine residues 41,46,47 , whose relevance in downstream signalling needs to be assessed.…”

Lumbar disc degeneration is linked to a carbohydrate sulfotransferase 3 variant

“…Numerous genetic risk factors for LDD have been reported and recently reviewed (17)(18)(19). There is moderate statistical evidence for ASPN (20), COL11A1 (21), GDF5 (22), SKT (23), THBS2 (24), and MMP9 (24), based on criteria for the assessment of genetic outcomes (25), with studies performed in cohorts of reasonable sample size and/or follow-up via replication or functional studies. Most of the genetic risk factors identified so far are from candidate gene studies, selected on the basis of our limited understanding of IVD biology in health and disease.…”

Generation of an 870 kb deletion encompassing the Skt/Etl4 locus by combination of inter- and intra-chromosomal recombination

“…However, at present it appears that in almost all expression domains the loss of Skt/Etl4 function can be compensated. The specific expression domain in the NP of the IVDs and strong association of SKT polymorphisms with Lumbar disc herniation (LDH) or Disc degeneration (DD) in Finish and Japanese populations [31, 32] makes SKT a good candidate for a LDH or DD susceptibility gene in humans. These studies did not mention other health problems in these patients, supporting that Skt/Etl4 function is only required for IVD formation or stability.…”

“…These studies did not mention other health problems in these patients, supporting that Skt/Etl4 function is only required for IVD formation or stability. However, it is still unclear how the LDH associated and intronic SNPs influence SKT/ETL4 function in the patients [31]. …”