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NDRG1
N-myc downstream regulated 1
NDRG1 is located on the long (q) arm of chromosome 8, at band 8q24.22. Arm ratio per GRCh38 - banding schematic.
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Overview
NDRG1 (N-myc downstream regulated 1) encodes a widely expressed protein that participates in cellular stress responses, particularly under conditions of low oxygen availability. The protein is highly abundant in Schwann cells, the specialised cells that produce myelin in the peripheral nervous system. Research suggests that NDRG1 coordinates multiple cellular pathways, including responses to nutrient deprivation and maintenance of cellular differentiation. The gene's importance for human health became evident through its association with hereditary peripheral neuropathies, conditions affecting the nerves outside the brain and spinal cord.
What the gene does
The NDRG1 protein functions as a stress-responsive molecule that helps cells adapt to challenging environmental conditions. Evidence suggests the protein plays particularly important roles in Schwann cells, where it contributes to the formation and maintenance of myelin sheaths surrounding peripheral nerve axons. NDRG1 appears to coordinate cellular responses to hypoxia, helping cells adjust their metabolism when oxygen becomes limited. The protein also participates in regulating cell growth and differentiation, with studies indicating it may influence pathways controlling cell cycle progression. In the peripheral nervous system, NDRG1 is essential for maintaining proper nerve function, with its absence or dysfunction leading to progressive myelin degradation and impaired nerve signalling.
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Chromosome location
NDRG1 is located on chromosome 8 at position 8q24.22, near the long arm terminus of the chromosome. The gene comprises 16 exons spanning approximately 60 kilobases of genomic DNA. This chromosomal region contains several other genes involved in cellular regulation and metabolism.
Protein structure
The NDRG1 protein consists of 394 amino acids organised into several distinct structural features. The protein contains a Disordered region spanning amino acids 325-394 near the carboxy terminus. Within this disordered region lies a notable structural element comprising 3 X 10 AA tandem repeats of G-T-R-S-R-S-H-T-S-E, extending from amino acids 339-368. These repeats are individually designated as Repeat 1 (amino acids 339-348), Repeat 2 (amino acids 349-358), and Repeat 3 (amino acids 359-368). The presence of this disordered carboxy-terminal region with tandem repeats may contribute to the protein's ability to interact with multiple cellular partners and participate in diverse regulatory pathways.
Key variants
Pathogenic variants in NDRG1 have been identified throughout the gene's coding sequence, though certain regions appear more frequently affected in clinical cases. Loss-of-function variants, including nonsense mutations and frameshift deletions, typically result in absent or severely truncated protein products. Missense variants affecting conserved amino acid residues may disrupt protein stability or interfere with critical functional domains. Founder mutations have been reported in specific populations, reflecting historical genetic bottlenecks.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.205+1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | Charcot-Marie-Tooth disease type 4D |
c.205+1G>C | - | Pathogenic/Likely pathogenic | ★★☆☆ | Inborn genetic diseases |
c.237C>A | p.Tyr79Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Charcot-Marie-Tooth disease type 4D |
c.40A>T | p.Lys14Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Charcot-Marie-Tooth disease type 4D |
c.442C>T | p.Arg148Ter | Pathogenic | ★★☆☆ | Charcot-Marie-Tooth disease type 4 |
c.510_511insTGTGTGGA | p.Gly171fs | Pathogenic/Likely pathogenic | ★★☆☆ | Charcot-Marie-Tooth disease type 4 |
c.681dup | p.Ile228fs | Pathogenic/Likely pathogenic | ★★☆☆ | Charcot-Marie-Tooth disease |
c.944-1G>T | - | Pathogenic/Likely pathogenic | ★★☆☆ | Charcot-Marie-Tooth disease type 4D |
c.390-1G>A | - | Pathogenic | ★☆☆☆ | Charcot-Marie-Tooth disease type 4D |
c.880C>T | p.Gln294Ter | Pathogenic | ★☆☆☆ | Charcot-Marie-Tooth disease type 4D |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Biallelic pathogenic variants in NDRG1 cause hereditary motor and sensory neuropathy, also known as Charcot-Marie-Tooth disease type 4D. This autosomal recessive condition typically presents in childhood or early adolescence with progressive muscle weakness and sensory loss in the limbs. Affected individuals often develop difficulties with walking and hand coordination as peripheral nerve function deteriorates. The severity and progression rate can vary considerably between individuals, even those carrying identical variants. Hearing loss may also occur in some cases, reflecting NDRG1's role in maintaining myelin in both peripheral nerves and auditory pathways.
No disease links recorded for this gene in our reference set.
UK clinical status
NDRG1 is included on the NHS Genomic Medicine Service Hereditary neuropathy panel with green classification, indicating strong evidence supporting its role in inherited peripheral nerve disorders. The gene also appears on the Hereditary neuropathy or pain disorder panel (R78) with green status. This inclusion reflects the gene's established clinical validity for diagnosing hereditary neuropathies within the NHS, enabling patients with relevant clinical features to access genetic testing through appropriate clinical pathways.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What type of inheritance pattern does NDRG1 follow?
NDRG1-related conditions follow an autosomal recessive inheritance pattern, meaning affected individuals carry pathogenic variants in both copies of the gene (one inherited from each parent). Carriers with one pathogenic variant typically do not show symptoms.
At what age do NDRG1-related neuropathies typically appear?
Most individuals with NDRG1-related hereditary motor and sensory neuropathy develop symptoms during childhood or adolescence, though the precise age of onset and rate of progression can vary considerably between affected individuals.
How does NDRG1 protein support nerve function?
NDRG1 protein is highly expressed in Schwann cells, where it contributes to forming and maintaining the myelin sheaths that insulate peripheral nerve fibres. Without functional NDRG1, myelin gradually degenerates, impairing the nerve's ability to transmit signals efficiently.