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MEMBRANE-BOUND TRANSCRIPTION FACTOR PROTEASE, SITE 2; MBTPS2

MEMBRANE-BOUND TRANSCRIPTION FACTOR PROTEASE, SITE 2; MBTPS2

Alternative titles; symbolsSITE-2 PROTEASE; S2PHGNC Approved Gene Symbol: MBTPS2Cytogenetic location: Xp22.12 Genomic coordinates (GRCh38): X:21,839,616-21,8...

Alternative titles; symbols

  • SITE-2 PROTEASE; S2P

HGNC Approved Gene Symbol: MBTPS2

Cytogenetic location: Xp22.12 Genomic coordinates (GRCh38): X:21,839,616-21,885,422 (from NCBI)

▼ Description
MBTPS2 is a membrane-embedded zinc metalloprotease that activates signaling proteins involved in sterol control of transcription and endoplasmic reticulum (ER) stress response (Rawson et al., 1997; Zelenski et al., 1999).

▼ Cloning and Expression
Rawson et al. (1997) cloned MBTPS2, which they called S2P. The deduced 510-amino acid metalloprotease is required for intramembrane proteolysis of sterol regulatory element-binding proteins (SREBPs; see 184756) at site 2. SREBPs are membrane-bound transcription factors that activate genes regulating cholesterol metabolism. The active N-terminal domains of SREBPs are released from membranes by sequential cleavage at 2 sites: site 1 (see S1P, 603355), within the lumen of the endoplasmic reticulum, and site 2, within a transmembrane segment. The human S2P gene was cloned by complementation of mutant CHO cells that could not cleave SREBPs at site 2 and were cholesterol auxotrophs. S2P defines a family of polytopic membrane proteins that contain an HEXXH sequence characteristic of zinc metalloproteases. Mutation of the putative zinc-binding residues abolished S2P activity. S2P encodes an unusual metalloprotease that cleaves proteins within transmembrane segments.

▼ Mapping
By FISH, Rawson et al. (1997) mapped the MBTPS2 gene to the X chromosome. Aten et al. (2010) noted that the MBTPS2 gene maps to chromosome Xp22.12-p22.11.

▼ Gene Function
Zelenski et al. (1999) used protease protection and glycosylation site mapping to define the topology of S2P in ER membranes. Both the N and C termini of S2P face the cytosol. Most of S2P is hydrophobic and appears to be buried in the membrane. All 3 of the long hydrophilic sequences of S2P can be glycosylated, indicating that they all project into the lumen. The HEIGH sequence of S2P, which contains 2 potential zinc-coordinating residues, is contained within a long hydrophobic segment. Asp467, located approximately 300 residues away from the HEIGH sequence, appears to provide the third coordinating residue for the active-site zinc. This residue, too, is located in a hydrophobic sequence. The hydrophobicity of these sequences suggests that the active site of S2P is located within the membrane in an ideal position to cleave its target, a leu-cys bond in the first transmembrane helix of SREBPs.

Activating transcription factor-6 (ATF6; 605537) is a membrane-bound transcription factor that activates genes in the ER stress response. When unfolded proteins accumulate in the ER, ATF6 is cleaved to release its cytoplasmic domain, which enters the nucleus. Ye et al. (2000) showed that ATF6 is processed by S1P and S2P, the enzymes that process SREBPs in response to cholesterol deprivation. ATF6 processing was blocked completely in cells lacking S2P and partially in cells lacking S1P. ATF6 processing required RxxL and asparagine/proline motifs, known requirements for S1P and S2P processing, respectively. Cells lacking S2P failed to induce GRP78 (138120), an ATF6 target, in response to ER stress. ATF6 processing did not require SREBP cleavage-activating protein (SCAP; 601510), which is essential for SREBP processing. Ye et al. (2000) concluded that S1P and S2P are required for the ER stress response as well as for lipid synthesis.

▼ Biochemical Features
Crystal Structure

Escherichia coli GlpG is an integral membrane protein that belongs to the widespread rhomboid protease family, including S2P and gamma-secretase. Wang et al. (2006) described the 2.1-angstrom crystal structure of the GlpG core domain. This structure contains 6 transmembrane segments. Residues involved in catalysis, including a ser-his dyad, and several water molecules are found at the protein interior at a depth below the membrane surface. This putative active site is accessible by substrate through a large 'V-shaped' opening that faces laterally towards the lipid, but is blocked by a half-submerged loop structure. Wang et al. (2006) concluded that in intramembrane proteolysis, the scission of peptide bonds takes place within the hydrophobic environment of the membrane bilayer. The crystal structure also suggests a gating mechanism for GlpG that controls substrate access to its hydrophilic active site.

▼ Molecular Genetics
IFAP Syndrome 1, With or Without BRESHECK Syndrome

In affected members of 3 multigenerational families segregating IFAP syndrome-1 with or without the additional features of BRESHECK syndrome (IFAP1; 308205) and in 2 affected unrelated males, all of European descent, Oeffner et al. (2009) identified 5 different missense mutations in the MBTPS2 gene (see 300294.0001-300294.0005). All affected males had the IFAP triad of follicular ichthyosis, atrichia of the scalp, and photophobia. There was only minor intrafamilial phenotypic variability between male patients, whereas in different families, the clinical severity varied widely. Carrier females were either phenotypically normal or showed rather mild symptoms such as asymmetric distribution of body hair, patchy alopecia, or linear lesions of follicular ichthyosis after the lines of Blaschko. Functional studies demonstrated diminished activity of MBTPS2 that correlated with clinical severity in affected males.

In a 26-year-old Ashkenazi Jewish man and a 28-year-old Caucasian man who both exhibited the typical IFAP triad, Oeffner et al. (2011) identified an intronic mutation in the MBTPS2 gene (300294.0007). Minigene experiments as well as RT-PCR analysis with patient-derived mRNA demonstrated that the mutation caused skipping of exon 6.

In a Japanese boy with a clinical diagnosis of BRESHECK syndrome, Naiki et al. (2012) identified an R429H mutation in the MBTPS2 gene (300294.0003). His unaffected mother was heterozygous for the mutation. The patient had multiple severe congenital anomalies, including generalized alopecia, erythematous skin with continuous desquamation, photophobia, corneal erosions, dystrophic nails, hearing loss, and severely delayed psychomotor development. He also had Hirschsprung disease, imbalanced hemivertebrae in the 2 lowest thoracic vertebral bodies, and a small right kidney. Brain MRI at age 3 showed decreased volumes of the frontal and parietal lobes, thinning of the corpus callosum, and ventricular dilatation. At 4 years of age, he was bedridden and showed almost no response to people. The R429H mutation had previously been reported in a patient with severe IFAP (Oeffner et al., 2009), indicating that the 2 disorders are allelic and represent a phenotypic spectrum.

In a 22-year-old Han Chinese man with IFAP who also exhibited features of Olmsted syndrome (see 300918), Wang et al. (2014) identified the same intronic mutation in the MBTPS2 gene (300294.0007) that had previously been identified in 2 IFAP patients by Oeffner et al. (2011). Wang et al. (2014) designated the phenotype in their patient as 'IFAP with Olmsted syndrome-like features' and questioned whether X-linked Olmsted syndrome represented an independent condition or merely a severe form of IFAP.

X-linked Keratosis Follicularis Spinulosa Decalvans

In affected members of the original Dutch family with X-linked keratosis follicularis spinulosa decalvans (KFSDX; 308800) reported by Siemens (1926), Aten et al. (2010) identified a hemizygous mutation in the MBTPS2 gene (N508S; 300294.0006). Analysis of 2 additional families with the disorder from the U.K. and the U.S. identified the same mutation, although haplotype analysis did not suggest a common ancestor.

In 15 affected males with IFAP or KFSDX from 13 unrelated families, Bornholdt et al. (2013) identified 11 different missense mutations, including a Swedish boy with KFSDX who had the N508S mutation.

X-linked Olmsted Syndrome

In a consanguineous Iranian family in which an uncle and nephew had alopecia universalis and severe palmoplantar keratoderma with involvement of periorificial and extensor surfaces and onychodystrophy (OLMSX; 300918) and were negative for mutation in the TRPV3 (607066), GJB2 (121011), GJB3 (603324), GJB4 (605425), GJB6 (604418), DSP (125647), and JUP (173325) genes, Haghighi et al. (2013) performed whole-exome sequencing and identified a missense mutation in the MBTPS2 gene (F464S; 300294.0008). Female family members did not exhibit any clinical features of Olmsted syndrome, and the affected males did not have features specific to BRESHECK syndrome (see 308205) such as hearing loss, skeletal abnormalities, or dysmorphic features.

Osteogenesis Imperfecta, Type XIX

In 2 unrelated families segregating X-linked osteogenesis imperfecta (OI19; 301014), Lindert et al. (2016) identified 2 different missense mutations in the MBTPS2 gene (N459S, 300294.0009 and L505F, 300294.0010) that segregated with disease in each family and were not found in controls or in public variant databases. The authors noted that none of the affected individuals, even in adulthood, exhibited any of the dermatologic features previously reported in patients with MBTPS2 mutations. Functional analysis demonstrated that both mutations disrupt the processing of regulated intramembrane proteolysis substrates.

▼ ALLELIC VARIANTS ( 10 Selected Examples):

.0001 IFAP SYNDROME 1
MBTPS2, HIS277LEU
In affected males from a 3-generation pedigree segregating ichthyosis follicularis, alopecia, and photophobia (IFAP1; 308205), Oeffner et al. (2009) identified a 680A-T transversion in the MBTPS2 gene, resulting in a his227-to-leu (H227L) substitution. The mutation was not detected in 225 X chromosomes of unrelated individuals. Male patients mainly displayed the IFAP triad of symptoms comprising total alopecia, ichthyotic scaling, and pronounced photophobia. Functional studies with this mutation showed slightly diminished MBTPS2 activity. Obligate carrier females were either phenotypically normal or mildly affected.

.0002 IFAP SYNDROME 1
MBTPS2, MET87ILE
In affected members of a 4-generation family segregating IFAP syndrome (IFAP1; 308205), Oeffner et al. (2009) identified a 261G-A transition in the MBTPS2, resulting in a met87-to-ile (M87I) substitution. The mutation was not identified in 225 control X chromosomes. Male patients mainly displayed the IFAP triad of symptoms comprising total alopecia, ichthyotic scaling, and pronounced photophobia. Functional studies with this mutation showed slightly diminished MBTPS2 activity. Obligate carrier females were either phenotypically normal or mildly affected.

.0003 IFAP SYNDROME 1
MBTPS2, ARG429HIS
In affected members of a 3-generation pedigree segregating IFAP syndrome with additional features consistent with BRESHECK syndrome (IFAP1; 308205), Oeffner et al. (2009) identified a 1286G-A transition in the MBTPS2 gene, resulting in an arg429-to-his (R429H) substitution. The mutation was not identified in 225 X chromosomes from unrelated individuals. Male patients had a severe form of the disorder, with multiple additional malformations and death within 2 years of birth. One male was a collodion baby who also had cleft palate, unilateral cleft hand, 2 butterfly vertebrae, absence of a kidney, and bilateral inguinal hernia, omphalocele, stenosis of small intestine, and Hirschsprung disease. Another had IFAP triad, microcephaly, arachnoid cyst, Arnold-Chiari malformation type I, thoracolumbar hydromyelia, seizures, psychomotor retardation, retrognathia, deficient growth, cleft hands, butterfly vertebra, wedge-shaped vertebra, atrial septal defect, arterial hypertension, recurrent infections of upper airways, absence of a kidney, hypospadias, choanal stenosis, inguinal hernia, and Hirschsprung disease Obligate carrier females were either phenotypically normal or mildly affected. Functional studies with this mutation showed almost no MBTPS2 activity.

In a Japanese boy with a clinical diagnosis of BRESHECK syndrome, Naiki et al. (2012) identified an R429H mutation in the MBTPS2 gene (300294.0003). His unaffected mother was heterozygous for the mutation. The patient had multiple severe congenital anomalies, including generalized alopecia, erythematous skin with continuous desquamation, photophobia, corneal erosions, dystrophic nails, hearing loss, and severely delayed psychomotor development. He also had Hirschsprung disease, imbalanced hemivertebrae in the 2 lowest thoracic vertebral bodies, and a small right kidney. Brain MRI at age 3 showed decreased volumes of the frontal and parietal lobes, thinning of the corpus callosum, and ventricular dilatation. At 4 years of age, he was bedridden and showed almost no response to people. The same mutation had previously been reported in a patient with severe IFAP (Oeffner et al., 2009), indicating that the 2 disorders are allelic and represent a phenotypic spectrum.

.0004 IFAP SYNDROME 1
MBTPS2, PHE475SER
In an affected member of a family segregating IFAP syndrome with BRESHECK syndrome (IFAP1; 308205), previously described by Boente et al. (2000), Oeffner et al. (2009) identified a 1424T-C transition in the MBTPS2 gene, resulting in a phe475-to-ser substitution. The mutation was not identified in 225 control X chromosomes from unrelated individuals. The patient had a severe form of the disorder with the additional features of seizures, mental retardation, and inguinal hernia. Functional studies with this mutation showed almost no MBTPS2 activity. Obligate carrier females were either phenotypically normal or mildly affected.

.0005 IFAP SYNDROME 1
MBTPS2, TRP226LEU
In an affected male from a family segregating IFAP syndrome (IFAP1; 308205), Oeffner et al. (2009) identified a 667G-T transversion in the MBTPS2 gene, resulting in a trp226-to-leu (W226L) substitution. The mutation was not identified in 225 X chromosomes from unrelated individuals. The patient mainly displayed the IFAP triad of symptoms comprising total alopecia, ichthyotic scaling, and pronounced photophobia. Obligate carrier females were either phenotypically normal or mildly affected. Functional studies with this mutation showed slightly diminished MBTPS2 activity.

.0006 KERATOSIS FOLLICULARIS SPINULOSA DECALVANS, X-LINKED
MBTPS2, ASN508SER
In affected members of the original Dutch family with X-linked keratosis follicularis spinulosa decalvans (KFSDX; 308800), Aten et al. (2010) identified a hemizygous 1523A-G transition in the MBTPS2 gene, resulting in an asn508-to-ser (N508S) substitution at a highly conserved hydrophobic transmembrane region. The same hemizygous mutation was identified in 2 additional families with the disorder, 1 from the U.K., originally described by Herd and Benton (1996), and 1 from the U.S. Haplotype analysis did not suggest a common ancestor. The mutation was not detected in 86 control chromosomes. In vitro functional expression studies in CHO-M19 cells showed that the mutation decreased sterol responsiveness by 50%, indicating loss of proteolytic activity of the MBTPS2 protein. Plasma lipid profile of an affected male showed no abnormalities. In obligate female carriers, imbalances in allelic expression perfectly matched with skewed levels of X inactivation and with the clinical phenotype. The findings suggested that KFSDX and IFAP syndrome (308205) are related along a similar disease spectrum.

In an 8-year-old Swedish boy with KFSDX, Bornholdt et al. (2013) identified the N508S mutation in the MBTPS2 gene. The patient had dry, itchy skin and photophobia at birth, with corneal dots noted at age 4 years; by age 8 years, he had widespread follicular hyperkeratosis, red cheeks, and thin eyebrows, with normal-appearing scalp hair. There were no other affected family members. X-chromosome SNP and microsatellite analysis in this family and the previously described Dutch family (Aten et al., 2010) indicated that the mutation arose on different genetic backgrounds in the 2 families.

.0007 IFAP SYNDROME 1
MBTPS2, c.671-9T-G
In a 26-year-old Ashkenazi Jewish man and a 28-year-old Caucasian man, who both exhibited the typical IFAP triad of ichthyosis follicularis, alopecia, and photophobia (IFAP1; 308205), Oeffner et al. (2011) identified a transversion (c.671-9T-G) in intron 5 of the MBTPS2 gene, predicted to disrupt a putative intronic splicing enhancer. SNP analysis supported an independent origin of the mutation in the 2 patients, and the mutation was not found in more than 100 controls. Minigene assay yielded a prominent 246-nucleotide band demonstrating exon skipping (Ile225LeufsTer25), as well as an additional faint 365-nucleotide fragment indicating inclusion of exon 6. However, cDNA amplification of exons 5 to 7 from patient cells showed total exclusion of exon 6.

In a 22-year-old Han Chinese man with IFAP who also exhibited features of Olmsted syndrome (see 300918), Wang et al. (2014) identified the c.671-9T-G intronic mutation in the MBTPS2 gene. The mutation was confirmed by Sanger sequencing to be heterozygous in his more mildly affected mother, and was not found in his unaffected father or sister or in 200 unrelated ethnically matched controls. Wang et al. (2014) considered this patient to represent a severe form of IFAP.

.0008 OLMSTED SYNDROME, X-LINKED (1 family)
MBTPS2, PHE464SER
In an uncle and nephew from a consanguineous Iranian family with alopecia universalis and severe palmoplantar keratoderma with involvement of periorificial and extensor surfaces and onychodystrophy (Olmsted syndrome, OLMSX; 300918), originally described by Yaghoobi et al. (2007), Haghighi et al. (2013) identified a c.1391T-C transition in exon 11 of the MBTPS2 gene, resulting in a phe464-to-ser (F464S) substitution at a highly conserved residue located 2 codons from the LDG motif. The mutation, which segregated with disease in the family, was not found in the dbSNP, 1000 Genomes Project, NHLBI Exome Sequencing Project, or MBTPS2 gene variant databases.

.0009 OSTEOGENESIS IMPERFECTA, TYPE XIX
MBTPS2, ASN459SER
In a large Thai pedigree (family I) segregating X-linked osteogenesis imperfecta (OI19; 301014), Lindert et al. (2016) identified a c.1376A-G transition (c.1376A-G, NM_015884.3) in exon 11 of the MBTPS2 gene, resulting in an asn459-to-ser (N459S) substitution at the highly conserved first residue of the intramembrane NPDG motif. The mutation segregated fully with disease in the family and was not found in 644 X chromosomes of unrelated Thai controls or in the Leiden Open Variation, ExAC, Exome Variant Server, 1000 Genomes Project, or dbSNP (build 144) databases. Proband fibroblasts and osteoblasts showed impaired OASIS (CREB3L1; 616215) cleavage, and expression of OASIS as well as its nuclear binding target, SMAD4 (600993), was decreased in patient osteoblasts. The authors stated that these findings, together with reduced expression of the osteoblast maturation marker alkaline phosphatase, indicate a broad defect in osteoblast differentiation. Proband fibroblasts also showed decreased secretion of type I collagen. In transfected CHO-M19 cells, activation of the regulated intramembrane proteolysis substrates ATF6 (605537) and SREBP (see 184756) during endoplasmic reticulum stress and sterol-free conditions, respectively, was significantly reduced with the N459S mutant compared to wildtype MBTPS2.

.0010 OSTEOGENESIS IMPERFECTA, TYPE XIX
MBTPS2, LEU505PHE
In a 26-year-old male proband and his affected maternal uncle from a German family (family II) segregating X-linked osteogenesis imperfecta (OI19; 301014), Lindert et al. (2016) identified a c.1515G-C transversion (c.1515G-C, NM_015884.3) in the MBTPS2 gene, resulting in a leu505-to-phe (L505F) substitution at a highly conserved intramembrane residue. The proband's unaffected mother was heterozygous for the mutation, which was not found in the Leiden Open Variation, ExAC, Exome Variant Server, 1000 Genomes Project, or dbSNP (build 144) databases. Proband fibroblasts showed impaired OASIS (CREB3L1; 616215) cleavage as well as decreased type I collagen secretion. In transfected CHO-M19 cells, activation of regulated intramembrane proteolysis substrates ATF6 (605537) and SREBP (see 184756) during endoplasmic reticulum stress and sterol-free conditions, respectively, was significantly reduced with the L505F mutant compared to wildtype MBTPS2. Type I collagen extracted from proband bone had significantly reduced hydroxylation of helical lysine residue 87 (K87) in both alpha chains; the authors noted that K87 is critical for collagen crosslinking in bone, which is a major contributor to bone strength.

Tags: Xp22.12