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  • 总部: 泰国曼谷市巴吞汪区仑披尼分区 普勒吉路齐隆巷5号.
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DUAL SERINE/THREONINE AND TYROSINE PROTEIN KINASE; DSTYK

DUAL SERINE/THREONINE AND TYROSINE PROTEIN KINASE; DSTYK

Alternative titles; symbolsRECEPTOR-INTERACTING SERINE/THREONINE KINASE 5; RIPK5KIAA0472RECEPTOR-INTERACTING PROTEIN 5; RIP5DUSTY PROTEIN KINASE; DUSTYPKHGNC App...

Alternative titles; symbols

  • RECEPTOR-INTERACTING SERINE/THREONINE KINASE 5; RIPK5
  • KIAA0472
  • RECEPTOR-INTERACTING PROTEIN 5; RIP5
  • DUSTY PROTEIN KINASE; DUSTYPK

HGNC Approved Gene Symbol: DSTYK

Cytogenetic location: 1q32.1 Genomic coordinates (GRCh38): 1:205,142,496-205,211,701 (from NCBI)

▼ Cloning and Expression
By sequencing clones obtained from a size-fractionated brain cDNA library, Seki et al. (1997) cloned partial DSTYK, which they designated KIAA0472.

By EST database analysis, Zha et al. (2004) identified DSTYK, which they called RIP5. The deduced 929-amino acid protein contains a C-terminal kinase domain, which shares homology with the kinase domain of RIPK family members (see RIPK1; 603453). Northern blot analysis of human tissues detected weak expression in heart, brain, placenta, skeletal muscle, kidney, pancreas, and testis.

Sanna-Cherchi et al. (2013) found widespread membrane-associated distribution of Dstyk in mouse embryonic mesenchymal tissues, such as heart, lung, liver, colon, and skin. In the kidney, Dstyk was expressed at low levels in the nephrogenic zone, at higher levels in the maturing tubular epithelia, and showed most prominent expression in the medulla and papilla. DSTYK was found in the basolateral and apical membranes of all tubular epithelia in postnatal mouse and human pediatric kidneys. It was also detected in all layers of transitional ureteric epithelium and in ureteric smooth muscle cells.

▼ Mapping
Gross (2015) mapped the DSTYK gene to chromosome 1q32.1 based on an alignment of the DSTYK sequence (GenBank BC053627) with the genomic sequence (GRCh38).

▼ Gene Function
Zha et al. (2004) demonstrated by in vitro kinase assay that DSTYK did not exhibit autophosphorylation activity. DSTYK failed to activate NF-kappa-B (NFKB1; 164011) in a reporter gene assay. Overexpression of DSTYK induced DNA fragmentation and cell death in a dose-dependent manner with cell death occurring approximately 30 hours after transfection. Caspase inhibitory protein and morphologic studies showed that DSTYK induced both caspase-dependent and caspase-independent cell death, and both the N- and C-terminal DSTYK deletion mutants retained the ability to induce cell death.

In the developing mouse nephron, Sanna-Cherchi et al. (2013) found that Dstyk colocalized with both FGFR1 (136350) and FGFR2 (176943) in the ureteric bud and in comma-shaped bodies. Colocalization with FGFR2 was also evident in distal tubular cells in the adult renal medulla and papilla. Punctate Dstyk staining was seen at apical cell-cell junctions lining the ureteric-bud epithelia. Sanna-Cherchi et al. (2013) suggested that Dstyk acts as a positive regulator of FGF (see 131220)-mediated signaling in the kidney. In HEK293T cells, siRNA knockdown of DSTYK prevented FGF-induced phosphorylation of ERK (600997), suggesting that DSTYK works downstream of FGF signaling. However, coimmunoprecipitation studies with anti-FGFR2 antibodies did not show complex formation between FGFR2 and DSTYK, indicating that the effect was not mediated by a direct physical interaction.

▼ Molecular Genetics
Congenital Anomalies of the Kidney And Urinary Tract 1

In 7 affected members of a Sardinian family (K100) with congenital anomalies of the kidney and urinary tract-1 (CAKUT1; 610805), originally reported by Sanna-Cherchi et al. (2007), Sanna-Cherchi et al. (2013) identified a heterozygous splice site mutation in the DSTYK gene (612666.0001). The mutation, which was found by combining linkage analysis and whole-exome sequencing, was confirmed by Sanger sequencing. The mutation was not present in 5 unaffected family members, but was present in 2 unaffected adults and in 4 family members with an unknown phenotype, suggesting incomplete penetrance. Heidet et al. (2017) called into question the pathogenicity of this splice site variant. By sequencing of the DSTYK gene in 311 additional patients with CAKUT, Sanna-Cherchi et al. (2013) found 5 additional heterozygous mutations (see, e.g., 612666.0002-612666.0004) in 7 (2.3%) patients. None of these mutations were found in public databases or in 384 European controls. Clinical features included renal agenesis, renal hypodysplasia, ureteropelvic junction obstruction, or vesicoureteral reflux. DSTYK mutations predicted to be damaging were found in 14 (0.3%) of 4,300 white controls from the NHLBI Exome Variant Server. Sanna-Cherchi et al. (2013) concluded that carrying a heterozygous DSTYK mutation confers an odds ratio of 7.1 for CAKUT (p = 0.0003).

Spastic Paraplegia 23, Autosomal Recessive

In affected members of 3 unrelated families of Middle Eastern descent with spastic paraplegia-23 (SPG23; 270750), Lee et al. (2017) identified a homozygous intragenic deletion/insertion in the DSTYK gene (612666.0005). The deletion, which was found by a combination of whole-exome sequencing, homozygosity analysis, and copy number variation analysis in the first family, segregated with the disorder in all 3 families. Haplotype analysis indicated a founder effect. Cells from 1 patient showed decreased levels of DSTYK, suggesting a loss-of-function effect, and patient cells showed increased susceptibility to caspase-dependent apoptosis in response to UV stress compared to controls. One patient had a horseshoe kidney, but another patient had normal renal imaging; no heterozygous carriers were reported to have urinary tract abnormalities.

▼ Animal Model
Sanna-Cherchi et al. (2013) demonstrated that morpholino knockdown of the Dstyk ortholog in zebrafish embryos resulted in growth retardation, small fins, abnormal morphogenesis of the tail, and loss of heartbeat. also Mutant zebrafish also had cloacal malformations that corresponded to lower genitourinary defects in mammals and defects in jaw development, as well as specific loss of the median fin fold. Pericardial effusion was evident in 5-day-old morphant larvae, which was attributable to both heart and kidney failure. These data suggested an essential role of Dstyk in the development of major organs. The developmental defects resembled phenotypes produced by global loss of FGF signaling.

▼ ALLELIC VARIANTS ( 5 Selected Examples):

.0001 RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE
DSTYK, IVS2DS, G-A, +1
This variant, formerly titled CONGENITAL ANOMALIES OF KIDNEY AND URINARY TRACT, SUSCEPTIBILITY TO, 1, has been reclassified based on the report of Heidet et al. (2017).

In affected members of a Sardinian family (K100) with congenital anomalies of the kidney and urinary tract-1 (CAKUT1; 610805), originally reported by Sanna-Cherchi et al. (2007), Sanna-Cherchi et al. (2013) identified a heterozygous G-to-A transition in intron 2 of the DSTYK gene (c.654+1G-A), resulting in a splice site mutation. Mutation carriers had a 27-bp deletion within exon 2, resulting in an in-frame deletion of 9 amino acids in a domain that is highly conserved among mammals. The mutation, which was found linkage analysis and whole-exome sequencing, was confirmed by Sanger sequencing and was not found in 48 persons of Sardinian ancestry or 384 European controls. The mutation was not present in 5 unaffected family members, but was present in 2 unaffected adults and in 4 family members with an unknown phenotype, suggesting incomplete penetrance.

Heidet et al. (2017) identified the c.654+1 variant in a patient with branchiootic abnormalities but a normal renal ultrasound. The variant was found in 1 of 3,563 European exomes in the ExAC database and in 11 individuals without renal abnormalities in an in-house exome database. The findings called into question whether the variant is indeed pathogenic.

.0002 CONGENITAL ANOMALIES OF KIDNEY AND URINARY TRACT 1
DSTYK, TRP8TER
In a Macedonian boy with congenital anomalies of kidney and urinary tract (CAKUT1; 610805) manifest as ureteropelvic junction obstruction, Sanna-Cherchi et al. (2013) identified a heterozygous c.24G-A transition in the DSTYK gene, resulting in a trp8-to-ter (W8X) substitution. The patient also had hearing loss and early-onset ataxia that resolved. The mutation was not found in several public databases or in 385 European controls. The patient was identified from a cohort of 311 unrelated patients with CAKUT.

.0003 CONGENITAL ANOMALIES OF KIDNEY AND URINARY TRACT 1
DSTYK, IVS2AS, C-T, -3
In 2 Italian sibs with congenital anomalies of kidney and urinary tract (CAKUT1; 610805) manifest as ureteropelvic junction obstruction, Sanna-Cherchi et al. (2013) identified a heterozygous C-to-T transition in intron 2 of the DSTYK gene (c.655-3C-T), predicted to result in a splice site mutation. The mutation was not found in several public databases or in 385 European controls. One of the patients was identified from a cohort of 311 unrelated patients with CAKUT.

.0004 CONGENITAL ANOMALIES OF KIDNEY AND URINARY TRACT 1
DSTYK, ARG29GLN
In 3 unrelated patients with congenital anomalies of kidney and urinary tract (CAKUT1; 610805), Sanna-Cherchi et al. (2013) identified a heterozygous c.86G-A transition in the DSTYK gene, resulting in an arg29-to-gln (R29Q) substitution at a highly conserved residue. The mutation was not found in several public databases or in 385 European controls. The first patient was an Albanian boy who had ureteropelvic junction obstruction. The second patient was an Italian boy who had renal hypodysplasia in utero and developed chronic renal failure. The third patient was an Albanian girl who presented with renal hypodysplasia at birth and also had congenital adrenal hyperplasia. None of these patients, who were identified from a cohort of 311 unrelated patients, had familial disease.

.0005 SPASTIC PARAPLEGIA 23, AUTOSOMAL RECESSIVE
DSTYK, 4-KB DEL AND 20-BP INS
In affected members of 3 unrelated families of Middle Eastern descent with spastic paraplegia-23 (SPG23; 270750), Lee et al. (2017) identified a homozygous intragenic deletion/insertion in intron 11 of the DSTYK gene: a 4-kb deletion (chr1.205,145,663-205,149,750, GRCh38) associated with a 20-bp insertion (chr1.205,141,774-205,141,793, GRCh38), resulting in the removal of the last 2 exons (exons 12 and 13) along with part of the 3-prime untranslated region. The deletion, which was found by a combination of whole-exome sequencing, homozygosity analysis, and copy number variation analysis in the first family, segregated with the disorder in all 3 families. Haplotype analysis indicated a founder effect. One of the families had previously been reported by Mukamel et al. (1985) and Blumen et al. (2003). Skin biopsy from 1 of the patients showed markedly decreased immunolabeling for DSTYK compared to controls. Transmission electron microscopy showed focal loss of melanocytes with some remaining melanocytes showing ultrastructural features of swollen mitochondria with abnormal cristae and cytoplasmic vacuoles. Other cell types also showed these changes, findings that were consistent with increased susceptibility to stress and cell death. Patient cells and mouse fibroblasts with siRNA-mediated knockdown of Dstyk showed increased signs of apoptosis and cell death after UV exposure compared to controls.

Tags: 1q32.1