[email protected] (受疫情影响,东南亚目前只开放曼谷诊所)
全周 (9AM - 5PM)

我们和你在一起

Extra info thumb
  • 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.
  • [email protected]
ASPARTIC PEPTIDASE, RETROVIRAL-LIKE 1; ASPRV1

ASPARTIC PEPTIDASE, RETROVIRAL-LIKE 1; ASPRV1

Alternative titles; symbolsSKIN ASPARTIC PROTEASE; SASPSASPaseTPA-INDUCIBLE ASPARTIC PROTEINASE; TAPSMUNOHGNC Approved Gene Symbol: ASPRV1Cytogenetic location: 2...

Alternative titles; symbols

  • SKIN ASPARTIC PROTEASE; SASP
  • SASPase
  • TPA-INDUCIBLE ASPARTIC PROTEINASE; TAPS
  • MUNO

HGNC Approved Gene Symbol: ASPRV1

Cytogenetic location: 2p13.3 Genomic coordinates (GRCh38): 2:69,932,716-70,087,374 (from NCBI)

▼ Cloning and Expression
By SDS-PAGE analysis of proteins expressed in epidermal differentiation, followed by peptide sequencing, and RT-PCR of a human keratinocyte cDNA library, Bernard et al. (2005) cloned SASP. The deduced 343-amino acid protein has a calculated molecular mass of 37 kD, and an alternate isoform of 259 amino acids has a molecular mass of 28.5 kD. SASP shares similarity with aspartyl proteases with a retroviral-type signature, such as the equine anemia virus (EIAV) protease. SASP contains a predicted N-myristoylation domain, a dileucine site, N-glycosylation, sulfation, phosphorylation, myristoylation, and amidation sites, and a putative transmembrane domain. SASP shares 87% amino acid homology with its mouse ortholog. Northern blot analysis of human tissues detected SASP expression primarily in skin with lower expression in brain. Western blot analysis of human epidermis detected 14-kD and 28-kD isoforms, and the authors suggested that the 14-kD form represents the activated protease while the 28-kD form is an epidermal proform SASP. Bernard et al. (2005) suggested that activation may be related to keratinocyte differentiation, and they noted a persistence of the inactivated form throughout the stratum corneum in psoriatic epidermis compared to normal epidermis.

▼ Gene Structure
Bernard et al. (2005) determined that the SASP gene contains a single exon with no introns and spans 2.35 kb.

▼ Mapping
By genomic sequence analysis, Bernard et al. (2005) mapped the ASPRV1 gene to chromosome 2p13.1.

▼ Gene Function
Using a fluorescence-based protease assay, Bernard et al. (2005) demonstrated SASP catalytic activity. They showed that recombinant 28-kD SASP catalyzed the hydrolysis of casein and primarily hydrolyzed 1 bond in the oxidized B chain of insulin at glu13-ala14. Recombinant 28-kD SASP autocatalytically generated an active 14-kD protein. Analysis of active-site directed mutations determined that SASP is a member of the aspartic protease family and that asp212 is the key active site amino acid. Bernard et al. (2005) noted that the HIV protease inhibitor indinavir inhibited SASP autoactivation activity while aspartic protease inhibitor pepstatine did not inhibit SASP autoactivation.

▼ Molecular Genetics
In 13 affected individuals from 4 unrelated families segregating autosomal dominant lamellar ichthyosis (ADLI; 146750), Boyden et al. (2020) identified heterozygosity for missense mutations in the ASPRV1 gene (611765.0001-611765.0003). Functional analysis showed accumulation of high molecular weight filaggrin (135940) products in keratinocytes transduced by each of the 3 mutant proteins, suggesting impaired filaggrin processing by these mutant forms of ASPRV1.

▼ Animal Model
Bauer et al. (2017) studied a 10-month-old female German Shepherd that developed scaling pruritic skin shortly after birth. Examination revealed generalized hypotrichosis and focal alopecia as well as generalized severe exfoliation of grayish scales and mild erythema. The dog's 6 littermates and parents were unaffected. Histopathologic analysis of affected skin revealed a severe laminar to compact orthokeratotic hyperkeratosis extending into the follicular infundibula. The keratin layers were multifocally exfoliating as large scales. The underlying epidermis was mildly hyperplastic. The authors noted that the histologic findings were consistent with a cornification disorder and an inherited nonepidermolytic ichthyosis. Genome sequencing was negative for mutation in 14 known ichthyosis-associated genes. Because ichthyosis had not previously been reported in the German Shepherd breed, the authors hypothesized that a de novo mutation event might have occurred. Refiltering analysis identified a de novo missense variant (c.1052T-C) in the ASPRV1 gene, which is involved in profilaggrin-to-filaggrin processing. The change was predicted to result in a leu351-to-pro (L351P) substitution at a highly conserved residue. Immunofluorescence staining demonstrated an abnormal filaggrin expression pattern, with diffuse staining across epidermal layers, as well as some nuclear staining indicating defective processing of profilaggrin.

▼ ALLELIC VARIANTS ( 3 Selected Examples):

.0001 ICHTHYOSIS, LAMELLAR, AUTOSOMAL DOMINANT
ASPRV1, ARG311PRO
In 5 affected members over 3 generations of a family (kindred 292) with autosomal dominant lamellar ichthyosis (ADLI; 146750), Boyden et al. (2020) identified heterozygosity for a c.932G-C transversion (c.932G-C, NM_152792) in the ASPRV1 gene, resulting in an arg311-to-pro (R311P) substitution at a highly conserved residue. The mutation was not found in 2 unaffected family members. Expression of the R311P mutant in human keratinocytes revealed the presence of a 20-kD form of ASPRV1 not seen in control keratinocytes. Immunoblotting with an antifilaggrin (135940) antibody demonstrated accumulation of high molecular weight filaggrin products in the transduced keratinocytes, suggesting impaired filaggrin processing by the R311P mutant. Immunolocalization of filaggrin in patient skin and skin from an age-matched control revealed tightly focused staining within the stratum granulosum of control skin, whereas affected skin showed strong signal in the expanded stratum granulosum and weak expression within the upper layers of the stratum spinosum.

.0002 ICHTHYOSIS, LAMELLAR, AUTOSOMAL DOMINANT
ASPRV1, LYS199GLU
In a mother and 2 sons (kindred 1055) with autosomal dominant lamellar ichthyosis (ADLI; 146750), Boyden et al. (2020) identified heterozygosity for a c.595A-G transition (c.595A-G, NM_152792) in the ASPRV1 gene, resulting in a lys199-to-glu (K199E) substitution at a highly conserved residue. The mutation was not found in the mother's parents, indicating that it arose de novo in her. Expression of the K199E mutant in human keratinocytes revealed the presence of a 20-kD form of ASPRV1 not seen in control keratinocytes. Immunoblotting with an antifilaggrin (135940) antibody demonstrated accumulation of high molecular weight filaggrin products in the transduced keratinocytes, suggesting impaired filaggrin processing by the K199E mutant.

.0003 ICHTHYOSIS, LAMELLAR, AUTOSOMAL DOMINANT
ASPRV1, PRO314THR
In the probands from 2 unrelated families, including the 3-generation German family originally reported by Traupe et al. (1984) (kindred 630) and kindred 1099, with autosomal dominant lamellar ichthyosis (ADLI; 146750), Boyden et al. (2020) identified heterozygosity for a c.940C-A transversion (c.940C-A, NM_152792) in the ASPRV1 gene, resulting in a pro314-to-thr (P314T) substitution at a highly conserved residue. The mutation was shown to have arisen de novo in the proband from kindred 1099; familial segregation was not reported for kindred 630. Expression of the P314T mutant in human keratinocytes revealed the presence of a 20-kD form of ASPRV1 not seen in control keratinocytes. Immunoblotting with an antifilaggrin (135940) antibody demonstrated accumulation of high molecular weight filaggrin products in the transduced keratinocytes, suggesting impaired filaggrin processing by the P314T mutant.

Tags: 2p13.3