craniotubular dysplasia, Ikegawa type

Summary

craniotubular dysplasia, Ikegawa type (MONDO:0859226) is a disease caused by TMEM53 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: TMEM53 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 4

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	craniotubular dysplasia, Ikegawa type
Mondo ID	MONDO:0859226
OMIM	619727
DOID	DOID:0112340
UMLS	C5575335
MedGen	1806238
GARD	0026671
Is cancer (heuristic)	no

Data availability: 4 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › skeletal dysplasia › craniotubular dysplasia, Ikegawa type

Related subtypes (118): osteochondrodysplasia, diaphyseal medullary stenosis-bone malignancy syndrome, fibular aplasia-ectrodactyly syndrome, cerebrocostomandibular syndrome, cleidorhizomelic syndrome, dyschondrosteosis-nephritis syndrome, dysplasia epiphysealis hemimelica, carpotarsal osteochondromatosis, Camurati-Engelmann disease, genochondromatosis, autosomal dominant osteosclerosis, Worth type, coxopodopatellar syndrome, Lenz-Majewski hyperostotic dwarfism, delayed membranous cranial ossification, metaphyseal dysplasia-maxillary hypoplasia-brachydacty syndrome, oculodentodigital dysplasia, Ollier disease, osteoglophonic dysplasia, parietal foramina with cleidocranial dysplasia, chondromalacia patellae, Currarino triad, Proteus syndrome, brachydactyly-elbow wrist dysplasia syndrome, tricho-dento-osseous syndrome, bird headed-dwarfism, Montreal type, Yunis-Varon syndrome, split hand-foot malformation 1 with sensorineural hearing loss, ghosal hematodiaphyseal dysplasia, hyperostosis corticalis generalisata, Larsen-like syndrome, B3GAT3 type, mesomelic dwarfism-cleft palate-camptodactyly syndrome, metaphyseal acroscyphodysplasia, metaphyseal dysostosis-intellectual disability-conductive deafness syndrome, familial osteodysplasia, Anderson type, pseudodiastrophic dysplasia, rhizomelic syndrome, Urbach type, Richieri Costa-Pereira syndrome, craniometadiaphyseal dysplasia, wormian bone type, Weaver syndrome, SHOX-related short stature, craniofrontonasal syndrome, Eiken syndrome, 2q37 microdeletion syndrome, skeletal dysplasia-epilepsy-short stature syndrome, rhizomelic dysplasia, Patterson-Lowry type, pelvic dysplasia-arthrogryposis of lower limbs syndrome, Marshall-Smith syndrome, baby rattle pelvis dysplasia, metaphyseal dysplasia, Braun-Tinschert type, genitopatellar syndrome, osteofibrous dysplasia, Larsen-like osseous dysplasia-short stature syndrome, pancreatic insufficiency-anemia-hyperostosis syndrome, microcephalic primordial dwarfism due to ZNF335 deficiency, Hartsfield-Bixler-Demyer syndrome, colobomatous microphthalmia-rhizomelic dysplasia syndrome, Tatton-Brown-Rahman overgrowth syndrome, tall stature-scoliosis-macrodactyly of the great toes syndrome, Catel-Manzke syndrome, cognitive impairment - coarse facies - heart defects - obesity - pulmonary involvement - short stature - skeletal dysplasia syndrome, skeletal overgrowth-craniofacial dysmorphism-hyperelastic skin-white matter lesions syndrome, complex lethal osteochondrodysplasia, amniotic band syndrome, metaphyseal anadysplasia, syndromic craniosynostosis, thin ribs-tubular bones-dysmorphism syndrome, dysplasia of head of femur, Meyer type, epimetaphyseal skeletal dysplasia, melorheostosis with osteopoikilosis, Cole-Carpenter syndrome, spondylometaphyseal dysplasia, omodysplasia, Bruck syndrome, osteopetrosis, congenital absence of upper arm and forearm with hand present, congenital absence of thigh and lower leg with foot present, congenital absence of both forearm and hand, congenital absence of both lower leg and foot, acheiria, apodia, chondroectodermal dysplasia with night blindness, TRPV4-related bone disorder, adactyly of foot, short stature-advanced bone age-early-onset osteoarthritis syndrome, McCune-Albright syndrome, parietal foramina, Sotos syndrome, dysspondyloenchondromatosis, autosomal recessive cutis laxa type 2, FGFR3-related chondrodysplasia, filamin-related bone disorder, short rib dysplasia, spondylodysplastic dysplasia, acromelic dysplasia, bent bone dysplasia, chondrodysplasia punctata, primary osteolysis, non-syndromic limb reduction defect, Robinow syndrome, synpolydactyly, acrocoxomesomelic dysplasia, bone dysplasia Moore type, bone dysplasia corpus callosum agenesis, type 2 collagenopathy, LRP5-related primary osteoporosis, SLC26A2-related skeletal dysplasia, COMP-related skeletal dysplasia, primordial dwarfism and slender bone disorder, polydactyly-syndactyly-triphalangism, lysosomal storage disease with skeletal involvement, abnormal mineralization disorder, calvarial doughnut lesions with bone fragility and spondylometaphyseal dysplasia, de la Chapelle dysplasia, mesomelic dysplasia-digital anomalies-intellectual disability syndrome, proximal femoral focal deficiency, rhizomelic dysplasia, Ain-Naz type, TRIP11-related skeletal dysplasia, FAM111A-related skeletal dysplasia

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

4 retrieved; paginated sample, class counts are floors:

2 uncertain significance, 1 pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
986737	NM_024587.4(TMEM53):c.219_222dup (p.Val75fs)	TMEM53	Pathogenic	criteria provided, single submitter
986738	NM_024587.4(TMEM53):c.62-5_62-3del	TMEM53	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2571596	NM_024587.4(TMEM53):c.707_715dup (p.Arg238_Arg239insLeuAlaArg)	TMEM53	Uncertain significance	criteria provided, single submitter
4846950	NM_024587.4(TMEM53):c.433G>C (p.Ala145Pro)	TMEM53	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 2 · Orphanet: 0 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
TMEM53	Strong	Autosomal recessive	craniotubular dysplasia, Ikegawa type	2

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TMEM53	HGNC:26186	ENSG00000126106	Q6P2H8	Transmembrane protein 53	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TMEM53	Transmembrane protein 53	Ensures normal bone formation, through the negative regulation of bone morphogenetic protein (BMP) signaling in osteoblast lineage cells by blocking cytoplasm-nucleus translocation of phosphorylated SMAD1/5/9 proteins.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TMEM53	Other/Unknown	no		DUF829_TMEM53, AB_hydrolase_fold

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
mucosa of transverse colon	1
right lobe of liver	1
sperm	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TMEM53	207	ubiquitous	marker	right lobe of liver, mucosa of transverse colon, sperm

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TMEM53	387

Structural data

PDB: 0 · AlphaFold-only: 1 · No structure: 0

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TMEM53	Q6P2H8	89.97

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 1 evidence-associated genes (0 with Reactome annotation).

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of nucleocytoplasmic transport	1	1872.4×	0.002	TMEM53
negative regulation of ossification	1	624.1×	0.003	TMEM53
negative regulation of osteoblast differentiation	1	295.6×	0.003	TMEM53
negative regulation of BMP signaling pathway	1	290.6×	0.003	TMEM53

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TMEM53	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	TMEM53

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
TMEM53	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.