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).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. The GenCC does not independently verify the submitted information. Though the information is obtained from sources believed to be reliable, no warranty, expressed or implied, is made regarding accuracy, adequacy, completeness, reliability or usefulness of any information. This disclaimer applies to both isolated and aggregate uses of the information. The information is provided on an "as is" basis, collected through periodic submission and therefore may not represent the most up-to-date information from the submitters. If you have questions about the medical relevance of information contained on this website, please see a healthcare professional; if you have questions about specific gene-disease claims, please contact the relevant sources; and if you have questions about the representation of the data on this website, please contact gencc@thegencc.org.