GeneBe

MBTPS2

protein-coding

membrane bound transcription factor peptidase, site 2

Gene summary

This gene encodes a intramembrane zinc metalloprotease, which is essential in development. This protease functions in the signal protein activation involved in sterol control of transcription and the ER stress response. Mutations in this gene have been associated with ichthyosis follicularis with atrichia and photophobia (IFAP syndrome); IFAP syndrome has been quantitatively linked to a reduction in cholesterol homeostasis and ER stress response.[provided by RefSeq, Aug 2009]

Previous symbols:
  • KFSD

MANE transcript

NM_015884.4

Inheritance

XL, AD

ClinVar variants

P:16U:204B:65

Top phenotype

Keratosis follicularis spinulosa decalvans, X-linked; IFAP syndrome 1 with or without BRESHECK syndrome; Olmsted syndrome, X-linked; Osteogenesis imperfecta, type XIX

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chrX:21,839,617-21,885,423

External References & Databases

Ensembl (ENSG00000012174)NCBI Gene (51360)OMIM (300294)HGNC:15455GenCCUniProt (O43462)AlphaFoldClinVar (MBTPS2)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~45.8 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

IFAP syndrome 1, with or without BRESHECK syndromeDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0100213

Submitter: ClinGen

Variants in MBTPS2 have been observed in males with X-linked IFAP syndrome with or without BRESHECK syndrome. This disease was initially characterized by the triad of Ichthyosis Follicularis, Atrichia, and Photophobia (IFAP syndrome). Later, variants in this gene were also observed in individuals with additional features, including Brain anomalies, severe mental Retardation, Ectodermal dysplasia, Skeletal malformations, Hirschsprung disease, Ear/eye anomalies, Cleft palate/cryptorchidism, and Kidney dysplasia/hypoplasia (BRESHECK syndrome). Evidence suggests that there is no difference in the molecular mechanism underlying IFAP and BRESHECK syndromes and they are within the same phenotypic spectrum. Therefore, for the purposes of this curation, they have been lumped into one disease entity, IFAP syndrome with or without BRESHECK syndrome. Neurodevelopmental features are commonly found in individuals with IFAP syndrome, including developmental delay (32%), intellectual disability (39%), seizures (28%), and hypotonia (8%) (PMID: 21600032). Since 2009, 11 MBTPS2 variants in 17 male probands with X-linked IFAP/BRESHECK syndrome have been reported in 11 publications. In addition to the classic triad of IFAP, all of them had neurodevelopmental phenotypes and were hemizygous for missense variants. Complementation analysis and luciferase reporter assays in cell culture demonstrated impaired protein function for the variants studied, with residual activity (PMID: 19361614, 23316014). These studies indicate a partial loss-of-function disease mechanism, and suggest that complete null alleles may cause embryonic lethality in hemizygous males. In summary, there is definitive evidence to support this gene-disease association. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on 11/16/2020 (SOP Version 8).

keratosis follicularis spinulosa decalvans, X-linkedLIMITED

Inheritance Pattern: XL

Disease ID:MONDO:0010637

Submitter: Ambry Genetics

IFAP syndrome 1, with or without BRESHECK syndromeSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0100213

Submitter: Ambry Genetics

osteogenesis imperfecta, type 19LIMITED

Inheritance Pattern: XL

Disease ID:MONDO:0049223

Submitter: Ambry Genetics

osteogenesis imperfecta, type 19STRONG

Inheritance Pattern: XL

Disease ID:MONDO:0049223

Submitter: PanelApp Australia

IFAP syndrome 1, with or without BRESHECK syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0100213

Submitter: Orphanet

Olmsted syndrome, X-linkedSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010486

Submitter: G2P

keratosis follicularis spinulosa decalvansDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0000136

Submitter: G2P

keratosis follicularis spinulosa decalvansSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0000136

Submitter: Orphanet

mutilating palmoplantar keratoderma with periorificial keratotic plaquesSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019014

Submitter: Orphanet

Olmsted syndrome, X-linkedLIMITED

Inheritance Pattern: XL

Disease ID:MONDO:0010486

Submitter: Ambry Genetics

BRESEK syndromeSUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0019414

Submitter: Orphanet

IFAP syndrome 1, with or without BRESHECK syndromeSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0100213

Submitter: PanelApp Australia

IFAP syndrome 1, with or without BRESHECK syndromeSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0100213

Submitter: Labcorp Genetics (formerly Invitae)

osteogenesis imperfecta, type 19STRONG

Inheritance Pattern: XL

Disease ID:MONDO:0049223

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Keratosis follicularis spinulosa decalvans, X-linked; IFAP syndrome 1 with or without BRESHECK syndrome; Olmsted syndrome, X-linked; Osteogenesis imperfecta, type XIXXL

Manifestation: Craniofacial; Dermatologic; Gastrointestinal; Musculoskeletal; Neurologic; Ophthalmologic; Renal

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 1552542; 10398262; 10694306; 8745901; 18984066; 19361614; 20672378; 22105905; 24313295; 27380894Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MBTPS2 variants in ClinVar

15 Conditions Cataloged
not providedTotal: 193
not specifiedTotal: 58
Inborn genetic diseasesTotal: 33
IFAP syndrome 1, with or without BRESHECK syndromeTotal: 17
MBTPS2-related disorderTotal: 16
Osteogenesis imperfecta, type 19Total: 6
Olmsted syndrome, X-linkedTotal: 5
Keratosis follicularis spinulosa decalvans, X-linkedTotal: 4

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_015884.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

EffectPLPVUSLBBSum
synonymous
31
clinvar
37
clinvar
3
clinvar
 71
missense
12
clinvar
4
clinvar
156
clinvar
22
clinvar
3
clinvar
 197
nonsense
3
clinvar
 3
start loss
0
frameshift
0
splice donor/acceptor (+/-2bp)
14
clinvar
 14
Total124204596285

Highest pathogenic variant AF is 9.261746e-7

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 24 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_015884.4RefSeqNP_056968.111MANE Select
ENST00000379484.10EnsemblENSP00000368798.511MANE Select
ENST00000365779.2EnsemblENSP00000368796.17Standard
ENST00000365779.3EnsemblENSP00000368796.17Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
mbtps2Danio rerio

Structure: lipid localization

Quality: disrupted

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Protein processing in endoplasmic reticulum - Homo sapiens (human)
  • Sterol Regulatory Element-Binding Proteins (SREBP) signalling
  • ATF6 (ATF6-alpha) activates chaperones
  • Metabolism of lipids
  • Unfolded Protein Response (UPR)

Biological Process

  • cholesterol metabolic process
  • endoplasmic reticulum unfolded protein response
  • membrane protein intracellular domain proteolysis
  • response to endoplasmic reticulum stress
  • ATF6-mediated unfolded protein response

Molecular Function

  • metalloendopeptidase activity
  • metal ion binding

Cellular Component

  • Golgi membrane
  • cytoplasm
  • endoplasmic reticulum membrane
  • integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000379484
Coding exons
11
Length
45789
Individuals with no LoFs
0
Homozygous LoFs
0
Heterozygous LoFs
0
Defined
0
p
0.00
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense2.091121940.5770.00001433365
Missense (PolyPhen)956.7420.15861962
Synonymous0.1366970.40.9790.000005091063
Loss of Function3.89017.60.000.00000125295

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American00.0absent
Ashkenazi Jewish00.0absent
East Asian00.0absent
Finnish00.0absent
European (Non-Finnish)00.0absent
South Asian00.0absent
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Intramembrane proteolysis of sterol-regulatory element- binding proteins (SREBPs) within the first transmembrane segment thereby releasing the N-terminal segment with a portion of the transmembrane segment attached. Site-2 cleavage comes after site-1 cleavage which takes place in the lumenal loop.;
Disease
DISEASE: Olmsted syndrome, X-linked (OLMSX) [MIM:300918]: A rare congenital disorder characterized by bilateral mutilating palmoplantar keratoderma and periorificial keratotic plaques with severe itching at all lesions. Diffuse alopecia, constriction of digits, and onychodystrophy have also been reported. Infections and squamous cell carcinomas can arise on the keratotic areas. The digital constriction may progress to autoamputation of fingers and toes. {ECO:0000269|PubMed:22931912}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Keratosis follicularis spinulosa decalvans X-linked (KFSDX) [MIM:308800]: A rare disorder affecting the skin and the eye. Affected men show thickening of the skin of the neck, ears, and extremities, especially the palms and soles, loss of eyebrows, eyelashes and beard, thickening of the eyelids with blepharitis and ectropion, and corneal degeneration. {ECO:0000269|PubMed:20672378}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Intolerance Scores

LoFtool
0.0889
RVIS EVS
-0.56
RVIS percentile EVS
19.31

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
S
Essential (gene trap)
K
Indispensability pred.
E
Indispensability score
0.843

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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