OFD1
protein-codingOFD1 centriole and centriolar satellite protein
Gene summary
This gene is located on the X chromosome and encodes a centrosomal protein. A knockout mouse model has been used to study the effect of mutations in this gene. The mouse gene is also located on the X chromosome, however, unlike the human gene it is not subject to X inactivation. Mutations in this gene are associated with oral-facial-digital syndrome type I and Simpson-Golabi-Behmel syndrome type 2. Many pseudogenes have been identified; a single pseudogene is found on chromosome 5 while as many as fifteen have been found on the Y chromosome. [provided by RefSeq, Aug 2016]
- CXorf5
- RP23
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~43.2 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: XL
Disease ID:MONDO:0010702
Submitter: Orphanet
Inheritance Pattern: XL
Disease ID:MONDO:0010702
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: XL
Disease ID:MONDO:0010431
Submitter: G2P
Inheritance Pattern: XL
Disease ID:MONDO:0010702
Submitter: G2P
Inheritance Pattern: XL
Disease ID:MONDO:0010265
Submitter: G2P
Inheritance Pattern: XL
Disease ID:MONDO:0010320
Submitter: G2P
Inheritance Pattern: XL
Disease ID:MONDO:1040039
Submitter: ClinGen
The OFD1 protein is a key regulator of ciliogenesis, both of primary and motile cilia. It localizes primarily at centrioles and centriolar satellites, and basal bodies, and is involved in stabilizing centrioles and ensuring proper cilia assembly. Most reported OFD1 variants are loss of function (indels with frameshift) and are inherited in an X-linked dominant manner. OFD1 has been associated with 4 different diseases: Retinitis pigmentosa 23, Joubert syndrome 10 (XL-JS), Orofaciodigital syndrome I (OFD1) and Primary Ciliary Dyskinesia (PCD). Simpson–Golabi–Behmel syndrome, type 2 has previously been associated with OFD1 (PMID: 16783569) but this association has been disputed (PMID: 29057530, 26545172) and has not been included in the lumped curation, pending further evidence. Intra-familial variability within these diseases has been reported and X inactivation studies have shown that skewed X inactivation could be partially involved in the pathogenesis of intrafamilial clinical variability. OFD1 interacts with the LCA5-encoded protein lebercilin. Mutations in LCA5 cause the Leber's congenital amaurosis (LCA), a rare inherited eye disease. The destabilization of lebercilin in conditions of OFD1 deficiency might be the basis of Retinitis pigmentosa 23 diagnoses in these patients. There is an inverse correlation between OFD1 mutant protein length and phenotypic severity, which could be explained by differences in binding to functionally interacting proteins and disruption of ciliary localization. All mutations before amino acid residue 631 are lethal for males and cause OFD1 syndrome in females. Male patients with the p.K948fs and p.E923fs mutations have JS and may live beyond the age of 30 years, whereas carrier females are not affected. In addition, variants in exons 20 and 21 have been associated with PCD with or without additional characteristics of JS, in male patients. To our knowledge, no female patients with PCD have been reported with variants in OFD1. Based on this data, the ID/Autism EP and the Motile Ciliopathies GCEP decided to lump together the RP, OFD1, XL-JS and PCD disease assertions under OFD1-related ciliopathy, a MONDO Disease Ontology that is inclusive of all four assertions. This decision has been made as OFD1 mutations cause Ciliopathy with differing severity of phenotype (OFD1 > XL-JS > PCD, OFD1 being the most severe); the phenotype depends on the position of the stop codon. Early stop variants likely correspond with the absence of protein because of nonsense-mediated mRNA decay (MND). Regarding the correlation of OFD1 and XLID, in Del Giudice et al. 2014 (PMID: 24884629) the authors identified patients displaying neurological symptoms and/or cognitive/behavioral abnormalities, brain structural anomalies in 88.7%, cognitive impairment in 68%, and associated neurological disorders and signs in 53% of cases. The most frequently observed structural brain anomalies included agenesis of the corpus callosum, neuronal migration/organization disorders, intracerebral cysts, porencephaly, and cerebellar malformations. The results from Del Giudice et al. 2014 support recently published findings indicating that CNS involvement in this condition is found in more than 60% of cases. Additionally, the authors described specific neuropsychological aspects such as reduced ability processing verbal information, slow thought process, difficulties in attention and concentration, and notably, long-term memory deficits which may indicate a specific role of OFD1 and/or primary cilia in higher brain functions. Thus the association of OFD1 and OFD1-related ciliopathy is definitive.
Inheritance Pattern: AR
Disease ID:MONDO:0010176
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0016575
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0019200
Submitter: Orphanet
Inheritance Pattern: XL
Disease ID:MONDO:0010320
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: XL
Disease ID:MONDO:0010431
Submitter: Labcorp Genetics (formerly Invitae)
Clinical Genomic Database (CGD)
Manifestation: Craniofacial; Dental; Dermatologic; Gastrointestinal; Genitourinary; Musculoskeletal; Neurologic; Pulmonary; 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
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to OFD1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_003611.3. 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.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 29 | 174 | 6 | 209 | ||
| missense | 6 | 9 | 525 | 81 | 8 | 629 |
| nonsense | 24 | 8 | 15 | 47 | ||
| start loss | 1 | 2 | 3 | |||
| frameshift | 53 | 25 | 6 | 1 | 85 | |
| splice donor/acceptor (+/-2bp) | 12 | 23 | 38 | 2 | 75 | |
| Total | 95 | 66 | 615 | 258 | 14 | 1048 |
Highest pathogenic variant AF is 0.00006057824
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_003602.1 | 23 | MANE Select | |
| Ensembl | ENSP00000344314.6 | 23 | MANE Select | |
| RefSeq | NP_001317138.1 | 22 | Standard | |
| RefSeq | NP_001317139.1 | 18 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| ofd1 | Danio rerio | Structure: otolith Quality: decreased size abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Regulation of PLK1 Activity at G2/M Transition
- Recruitment of mitotic centrosome proteins and complexes
- Loss of Nlp from mitotic centrosomes
- Loss of proteins required for interphase microtubule organization from the centrosome
- Centrosome maturation
Biological Process
- G2/M transition of mitotic cell cycle
- mitotic cell cycle
- centriole replication
- regulation of G2/M transition of mitotic cell cycle
- cilium assembly
Molecular Function
- protein binding
- identical protein binding
- alpha-tubulin binding
- gamma-tubulin binding
Cellular Component
- nucleus
- centrosome
- centriole
- cytosol
- cilium
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000340096
- Coding exons
- 23
- Length
- 34649
- Individuals with no LoFs
- 125686
- Homozygous LoFs
- 19
- Heterozygous LoFs
- 39
- Defined
- 125744
- p
- 0.000231
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.320 | 350 | 367 | 0.953 | 0.0000276 | 6701 |
| Missense (PolyPhen) | 62 | 89.368 | 0.69376 | 1990 | ||
| Synonymous | -0.508 | 143 | 135 | 1.06 | 0.0000105 | 1807 |
| Loss of Function | 4.91 | 7 | 40.9 | 0.171 | 0.00000309 | 719 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.000076 | 0.000062 | rare |
| Latino/Admixed American | 0.00062 | 0.00049 | rare |
| Ashkenazi Jewish | 0.0027 | 0.0020 | notable |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.00022 | 0.00016 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0.00045 | 0.00033 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Component of the centrioles controlling mother and daughter centrioles length. Recruits to the centriole IFT88 and centriole distal appendage-specific proteins including CEP164. Involved in the biogenesis of the cilium, a centriole-associated function. The cilium is a cell surface projection found in many vertebrate cells required to transduce signals important for development and tissue homeostasis. Plays an important role in development by regulating Wnt signaling and the specification of the left-right axis. Only OFD1 localized at the centriolar satellites is removed by autophagy, which is an important step in the ciliogenesis regulation (By similarity). {ECO:0000250}.;
- Disease
- DISEASE: Simpson-Golabi-Behmel syndrome 2 (SGBS2) [MIM:300209]: A severe variant of Simpson-Golabi-Behmel syndrome, a condition characterized by pre- and postnatal overgrowth (gigantism), facial dysmorphism and a variety of inconstant visceral and skeletal malformations. {ECO:0000269|PubMed:16783569}. Note=The disease may be caused by mutations affecting the gene represented in this entry.; DISEASE: Joubert syndrome 10 (JBTS10) [MIM:300804]: A disorder presenting with cerebellar ataxia, oculomotor apraxia, hypotonia, neonatal breathing abnormalities and psychomotor delay. Neuroradiologically, it is characterized by cerebellar vermian hypoplasia/aplasia, thickened and reoriented superior cerebellar peduncles, and an abnormally large interpeduncular fossa, giving the appearance of a molar tooth on transaxial slices (molar tooth sign). Additional variable features include retinal dystrophy and renal disease. {ECO:0000269|PubMed:19800048, ECO:0000269|PubMed:26477546}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Retinitis pigmentosa 23 (RP23) [MIM:300424]: A retinal dystrophy belonging to the group of pigmentary retinopathies. Retinitis pigmentosa is characterized by retinal pigment deposits visible on fundus examination and primary loss of rod photoreceptor cells followed by secondary loss of cone photoreceptors. Patients typically have night vision blindness and loss of midperipheral visual field. As their condition progresses, they lose their far peripheral visual field and eventually central vision as well. {ECO:0000269|PubMed:22619378}. Note=The disease may be caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.178
Intolerance Scores
- LoFtool
- 0.117
- RVIS EVS
- -0.18
- RVIS percentile EVS
- 40.56
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.810
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |