Gene Function

ATP-dependent 5'-3' helicase that preferentially unwinds RNA:DNA substrates over DNA:DNA substrates, playing a crucial role in resolving 5'-overhang RNA:DNA hybrids (R-loops) and promoting transcription termination. Plays a role in transcription regulation by its ability to modulate RNA Polymerase II (Pol II) binding to chromatin and through its interaction with proteins involved in transcription. Contributes to the mRNA splicing efficiency and splice site selection. Required for the resolution of R-loop RNA-DNA hybrid formation at G-rich pause sites located downstream of the poly(A) site, allowing XRN2 recruitment and XRN2-mediated degradation of the downstream cleaved RNA and hence efficient RNA polymerase II (RNAp II) transcription termination. Required for the 3' transcriptional termination of PER1 and CRY2, thus playing an important role in the circadian rhythm regulation (By similarity). Involved in DNA double-strand breaks damage response generated by oxidative stress. In association with RRP45, targets the RNA exosome complex to sites of transcription-induced DNA damage. Plays a role in the development and maturation of germ cells: essential for male meiosis, acting at the interface of transcription and meiotic recombination, and in the process of gene silencing during meiotic sex chromosome inactivation (MSCI) (By similarity). May be involved in telomeric stability through the regulation of telomere repeat-containing RNA (TERRA) transcription. Plays a role in neurite outgrowth in hippocampal cells through FGF8-activated signaling pathways. Inhibits retinoic acid-induced apoptosis Source: UniProt

Relationship to CMT

Unclassified AR
1 subtype
9q34.13

First described 2004

Subtype	Inheritance	Class	OMIM	Sentinel Publication
SubtypeCMT-SETX	Inheritanceautosomal recessive	ClassUnclassified Subtypes	OMIMn/a	Sentinel Publication DNA/RNA Helicase Gene Mutations in a Form of Juvenile Amyotrophic Lateral Sclerosis (ALS4). “Dominant mutations in SETX cause HMN/ALS4 (Chen and el., 2004)” –Inherited Neuropathies Consortium (INC), CMT in Depth: Hereditary Motor Neuropathies – https://www1.rarediseasesnetwork.org/cms/inc/Healthcare-Professionals/CMT 2004 · 10.1086/421054

Stored Identifiers

No HGNC Aliases

hgnc_idHGNC:445

ensembl_gene_idENSG00000107290

coords_grch38chr9:132261356-132355117

coords_grch37chr9:135136743-135230372

entrez_id23064

omim_gene608465

uniprot_idsQ7Z333

refseq_accessionNM_015046

mane_refseqNM_015046.7

mane_ensemblENST00000224140.6

External recordsHGNC:445OMIM 608465gnomADUniProt Q7Z333ClinGenClinVar P/LPOrphanetMANE NM_015046.7

EvidenceClinGen Definitive distal hereditary motor neuropathyPanelApp Green

ClinVar Variants

Pathogenic and likely pathogenic variants in SETX, as classified in ClinVar, are read live from NCBI. Only aggregate germline records are shown. Uncertain and conflicting classifications are not. Experts in CMT makes no claim to the accuracy of ClinVar data. This index is provided for informational purposes only.

Review stars are ClinVar’s measure of how well a classification is supported: four for a practice guideline, three for an expert panel review, two for agreement among multiple submitters, one for a single submitter with criteria provided, and none where no criteria were provided.

Reported in CMT

Reported in Other Diseases

Reported in a disease other than CMT. Listed apart rather than counted as CMT variants.

Variants w/o a Recorded Disease

Pathogenic or likely pathogenic in ClinVar, submitted without a disease recorded.

The Dorsal Root

A Name That Does Too Much Work

Jean-Martin Charcot's name appears throughout medicine, but nowhere does it create more confusion than in the foot. Learn why the CMT foot and Charcot neuroarthropathy, also known as Charcot foot, share a name yet differ in how they develop, appear, and are managed.

When Medicine Lost Its Compass

Evidence failed not because it was wrong, but because it was weaponized. I lived the downstream effects of that failure for more than a decade. This is what happens when medicine forgets that data always ends in a human being.

Error 404: Gene Not Found

CMT genetic testing often fails to identify the cause of the disease, even when comprehensive panels are used. Here, we discuss why this happens, what genetic tests can and cannot do, and why a negative result still matters.