RETREG1
protein-codingreticulophagy regulator 1
Gene summary
The protein encoded by this gene is a cis-Golgi transmembrane protein that may be necessary for the long-term survival of nociceptive and autonomic ganglion neurons. Mutations in this gene are a cause of hereditary sensory and autonomic neuropathy type IIB (HSAN IIB), and this gene may also play a role in susceptibility to vascular dementia. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Nov 2011]
- FAM134B
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~144.1 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0015364
Submitter: ClinGen
RETREG1, also known as FAM134B, was first reported in relation to autosomal recessive hereditary sensory and autonomic neuropathy type IIB (HSAN2B) in 2009 (PMID: 19838196). This family had four affected children and a history of consanguinity; a region of interest was identified via genome-wide homozygosity mapping, then sequencing of the 7 genes in the region identified a homozygous nonsense mutation in RETREG1 which was predicted to cause nonsense mediated decay (c.926C>G; p.S309X). This condition has since been described in at least 30 individuals across 15 unrelated families (PMIDs: 19838196, 21115472, 24327336, 3064365, 31737055, 33943063, 35332675, 37448294). Symptoms are variable but tend to be early-onset with impaired nociception, ulcerations of hands and feet, chronic osteomyelitis leading to progressive acro-osteolysis, and exclusively or predominantly axonal sensory neuropathy. At least one family has been described with renal disease (PMID: 37448294). All described causative variants to date are predicted to cause loss of function. Most individuals have homozygous mutations and a history of consanguinity, but one family is compound heterozygous (PMID: 33943063) and there is one case of uniparental disomy (PMID: 31737055). Ample experimental evidence supports RETREG1’s role in disease including expression data, functional alteration of non-patient cells, and a mouse model (PMIDs: 19838196, 26040720). Data clearly shows that RETREG1 is found in small and large neurons of mouse dorsal root ganglia and in N2a cells, and has significant overlap with giantin (PMID: 19838196). Knockdown of the protein leads to significantly smaller cis-Golgi apparatus, impaired cell proliferation, and increased apoptosis (PMID: 19838196). In the mouse model, knockdown mice were shown to have similar phenotypes to human patients (PMID: 26040720). Available evidence totals 15 points and has been replicated over time; therefore, RETREG1 is definitively associated with hereditary sensory and autonomic neuropathy type IIB (HSAN2B).
Inheritance Pattern: AR
Disease ID:MONDO:0013142
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0013142
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0019941
Submitter: Orphanet
Clinical Genomic Database (CGD)
Manifestation: Neurologic
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
Comments: Insensitivity to pain can result in injuries and infections
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to RETREG1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001034850.3. 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 | 1 | 110 | 2 | 113 | ||
| missense | 233 | 7 | 1 | 241 | ||
| nonsense | 9 | 1 | 4 | 14 | ||
| start loss | 1 | 1 | ||||
| frameshift | 8 | 2 | 2 | 12 | ||
| splice donor/acceptor (+/-2bp) | 2 | 5 | 7 | |||
| Total | 19 | 8 | 241 | 117 | 3 | 388 |
Highest pathogenic variant AF is 0.000009926728
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001030022.1 | 9 | MANE Select | |
| Ensembl | ENSP00000304642.9 | 9 | MANE Select | |
| RefSeq | NP_061873.2 | 7 | Standard | |
| Ensembl | ENSP00000382691.2 | 7 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Biological Process
- sensory perception of pain
- negative regulation of neuron apoptotic process
- reticulophagy
Molecular Function
- protein binding
Cellular Component
- nucleolus
- endoplasmic reticulum
- cis-Golgi network
- nuclear body
- integral component of endoplasmic reticulum membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000306320
- Coding exons
- 9
- Length
- 144021
- Individuals with no LoFs
- 124770
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 24
- Defined
- 124794
- p
- 0.0000962
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.597 | 214 | 240 | 0.891 | 0.0000112 | 3233 |
| Missense (PolyPhen) | 60 | 81.851 | 0.73304 | 1167 | ||
| Synonymous | 0.272 | 90 | 93.3 | 0.964 | 0.00000452 | 960 |
| Loss of Function | 2.06 | 12 | 22.5 | 0.533 | 0.00000104 | 283 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00019 | 0.00019 | rare |
| Latino/Admixed American | 0.00018 | 0.00017 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00017 | 0.00017 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000062 | 0.000062 | rare |
| South Asian | 0.00013 | 0.00013 | rare |
| Other | 0.00017 | 0.00016 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Endoplasmic reticulum-anchored autophagy receptor that mediates ER delivery into lysosomes through sequestration into autophagosomes (PubMed:26040720). Promotes membrane remodeling and ER scission via its membrane bending capacity and targets the fragments into autophagosomes via interaction with ATG8 family proteins (PubMed:26040720). Required for long-term survival of nociceptive and autonomic ganglion neurons (PubMed:19838196, PubMed:26040720). {ECO:0000269|PubMed:19838196, ECO:0000269|PubMed:26040720}.;
- Disease
- DISEASE: Neuropathy, hereditary sensory and autonomic, 2B (HSAN2B) [MIM:613115]: A form of hereditary sensory and autonomic neuropathy, a genetically and clinically heterogeneous group of disorders characterized by degeneration of dorsal root and autonomic ganglion cells, and by sensory and/or autonomic abnormalities. HSAN2B is an autosomal recessive disorder characterized by impairment of pain, temperature and touch sensation. Onset occurs in the first or second decade, with impaired nociception and progressive mutilating ulceration of the hands and feet with osteomyelitis and acroosteolysis. Amputations of the hands and feet are common. Autonomic dysfunction includes hyperhidrosis, urinary incontinence, and slow pupillary light response. {ECO:0000269|PubMed:19838196}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.109
Intolerance Scores
- RVIS EVS
- 0.4
- RVIS percentile EVS
- 76.15
Essentials
- Essential (gene trap)
- N