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SPROUTY RTK SIGNALING ANTAGONIST 4; SPRY4

SPROUTY RTK SIGNALING ANTAGONIST 4; SPRY4

Alternative titles; symbolsSPROUTY, DROSOPHILA, HOMOLOG OF, 4HGNC Approved Gene Symbol: SPRY4Cytogenetic location: 5q31.3 Genomic coordinates (GRCh38): 5:142...

Alternative titles; symbols

  • SPROUTY, DROSOPHILA, HOMOLOG OF, 4

HGNC Approved Gene Symbol: SPRY4

Cytogenetic location: 5q31.3 Genomic coordinates (GRCh38): 5:142,310,429-142,325,020 (from NCBI)

▼ Description
SPRY4 is an inhibitor of the receptor-transduced mitogen-activated protein kinase (MAPK) signaling pathway. It is positioned upstream of RAS (see HRAS; 190020) activation and impairs the formation of active GTP-RAS (Leeksma et al., 2002).

▼ Cloning and Expression
By differential display RT-PCR of activated versus resting umbilical artery smooth muscle cells, Leeksma et al. (2002) isolated cDNAs encoding SPRY4. A 4.9-kb cDNA represents the major transcript and encodes a deduced 322-amino acid protein. SPRY4 contains a prototypic cysteine-rich region, 3 potential Src homology-3 (SH3)-binding proline-rich regions, and a PEST sequence. It shares 88% amino acid identity with mouse Spry4. Northern blot analysis detected expression of a 4.9-kb transcript in all tissues examined. In vitro transcription-translation yielded a protein with an apparent molecular mass of about 35 kD. Alternative splicing and use of an alternate polyadenylation site results in a 7.0-kb cDNA representing a transcript with a premature stop codon, due to a single-nucleotide shift. The deduced truncated protein contains 106 amino acids, and the transcript contains 5 polyadenylation sites, 9 ATTTA sequences, 2 Alu repeats, and 3 CAGAC motifs.

▼ Gene Structure
Khaitan et al. (2011) reported that a long noncoding RNA, SPRY4IT1 (617617), is transcribed from the second intron of the SPRY4 gene.

▼ Mapping
By FISH, Leeksma et al. (2002) mapped the SPRY4 gene to chromosome 5q31.3.

▼ Gene Function
Leeksma et al. (2002) found that SPRY4 suppressed the insulin receptor (147670)- and epidermal growth factor receptor (EGFR; 131550)-transduced MAPK signaling pathway, but it did not inhibit MAPK activation by a constitutively active mutant RAS. They concluded that SPRY4 impairs the formation of GTP-RAS. By yeast 2-hybrid screening and coimmunoprecipitation of transfected COS cells, Leeksma et al. (2002) determined that SPRY4 interacts with the C terminus of testis-specific protein kinase-1 (TESK1; 601782). This interaction increased following EGF (131530) stimulation. TESK1 and SPRY4 colocalized in peri- and paranuclear cytoplasmic puncta, but there was no substantial translocation to the plasma membrane upon receptor tyrosine kinase stimulation.

Sasaki et al. (2003) characterized mouse Spry4. They found that Spry4 suppressed vascular epithelial growth factor (VEGF; 192240)-induced, Ras-independent activation of Raf1 (164760), but it did not affect EGF-induced, Ras-dependent activation of Raf1. Spry4 bound Raf1 through its C-terminal cysteine-rich domain, and this binding was necessary for inhibition of Raf1 activation.

Unlike humans, who have a continuous row of teeth, mice have only molars and incisors separated by a toothless region called a diastema. Klein et al. (2006) showed that Spry2 (602466) in epithelium and Spry4 in mesenchyme prevent diastema tooth formation by preventing diastema tooth buds from engaging in the Fgf-mediated bidirectional signaling that normally sustains tooth development.

▼ Molecular Genetics
In 14 unrelated individuals with congenital hypogonadotropic hypogonadism (HH17; 615266), Miraoui et al. (2013) identified heterozygosity for missense mutations in the SPRY4 gene (see, e.g., 607984.0001-607984.0004). In 3 of the patients, their SPRY4 mutation was accompanied by a heterozygous missense mutation in another HH-associated gene, including FGFR1 (136350.0027) and DUSP6 (602748.0001 and 602748.0003). Miraoui et al. (2013) concluded that mutations in genes encoding components of the FGF pathway are associated with complex modes of congenital HH (CHH) inheritance and act primarily as contributors to an oligogenic genetic architecture underlying CHH.

Associations Pending Confirmation

For discussion of a possible association between variation in the SPRY4 gene and craniosynostosis, see 123100.

▼ ALLELIC VARIANTS ( 4 Selected Examples):

.0001 HYPOGONADOTROPIC HYPOGONADISM 17 WITH ANOSMIA
SPRY4, LYS177ARG (rs78310959)
In 4 male patients, 3 sporadic and 1 familial, with congenital hypogonadotropic hypogonadism (HH17; 615266), Miraoui et al. (2013) identified heterozygosity for a c.530A-G transition in exon 3 of the SPRY4 gene, resulting in a lys177-to-arg (K177R) substitution at a highly conserved residue in the link between the phosphotyrosine-binding and SPRY translocation domains. The mutation was not found in 155 controls, but was present in the 1000 Genomes Project at a minor allele frequency of 0.3%. All 4 patients were anosmic, and 1 also had hearing loss and 1 had abnormal dentition.

.0002 HYPOGONADOTROPIC HYPOGONADISM 17 WITH OR WITHOUT ANOSMIA, SUSCEPTIBILITY TO
SPRY4, SER241TYR (rs139512218)
In 4 patients with congenital hypogonadotropic hypogonadism (HH17; 615266), 3 female and 1 male, Miraoui et al. (2013) identified heterozygosity for a c.722C-A transversion in exon 3 of the SPRY4 gene, resulting in a ser241-to-tyr (S241Y) substitution at a highly conserved residue in the SPRY translocation domain. The mutation was found in 1 of 155 controls (minor allele frequency, 0.6%) and was reported in the 1000 Genomes Project at an MAF of 0.8%. Three of the patients were anosmic; those 3 patients also carried a heterozygous missense mutation in another HH-associated gene: 2 in DUSP6 (602748.0001 and 602748.0003) and 1 in FGFR1 (136350.0027). Additional features in the 3 anosmic patients included 2 with low bone mass and 1 with hearing loss. The remaining female patient was normosmic; she also had low bone mass as well as abnormal dentition.

.0003 HYPOGONADOTROPIC HYPOGONADISM 17 WITHOUT ANOSMIA
SPRY4, VAL16ILE
In a normosmic male patient with congenital hypogonadotropic hypogonadism (HH17; 615266), Miraoui et al. (2013) identified heterozygosity for a c.46G-A transition in exon 3 of the SPRY4 gene, resulting in a val16-to-ile (V16I) substitution in the N terminus. The mutation was not found in 155 controls or the 1000 Genomes Project.

.0004 HYPOGONADOTROPIC HYPOGONADISM 17 WITHOUT ANOSMIA
SPRY4, VAL304ILE
In a female patient with congenital hypogonadotropic hypogonadism (HH17; 615266), Miraoui et al. (2013) identified heterozygosity for a c.910G-A transition in exon 3 of the SPRY4 gene, resulting in a val304-to-ile (V304I) substitution at a highly conserved residue in the C terminus. The mutation was not found in 155 controls or the 1000 Genomes Project. This normosmic patient underwent partial puberty.

Tags: 5q31.3