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DDHD2
DDHD domain containing 2
DDHD2 is located on the short (p) arm of chromosome 8, at band 8p11.23. Arm ratio per GRCh38 - banding schematic.
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Overview
DDHD2 encodes DDHD domain containing 2, a phospholipase enzyme that plays a crucial role in maintaining lipid homeostasis within the nervous system. The protein belongs to a family of intracellular lipases that regulate the breakdown of phosphatidic acid and other membrane lipids. Pathogenic variants in DDHD2 are associated with a spectrum of neurological conditions, including hereditary spastic paraplegia and cerebellar ataxia. These conditions typically manifest as progressive motor impairment affecting gait, balance, and muscle tone. The gene is relevant to clinical genetics panels focused on neurogenetics and movement disorders in the UK.
What the gene does
The DDHD2 protein functions as a phospholipase enzyme with specificity for phosphatidic acid, a lipid molecule involved in cellular signalling and membrane dynamics. The enzyme catalyses the hydrolysis of phosphatidic acid to produce lysophosphatidic acid and free fatty acids, both of which serve as important signalling molecules and metabolic intermediates. This activity is particularly critical in neurons, where tight regulation of membrane lipid composition supports normal synaptic function and axonal transport. The protein localises to intracellular membranes, including the endoplasmic reticulum and lipid droplets, where it contributes to lipid remodelling processes. Loss of DDHD2 function leads to abnormal accumulation of lipid species, which appears to compromise neuronal integrity over time, particularly affecting the long axons of spinal motor neurons and cerebellar pathways.
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Chromosome location
DDHD2 is located on chromosome 8 at band 8p11.23. This chromosomal region contains multiple genes, and the DDHD2 locus spans several kilobases of genomic DNA. The gene is transcribed and translated into a protein of 711 amino acids.
Protein structure
The DDHD2 protein comprises 711 amino acids organised into several functional and structural domains. The N-terminal region contains a WWE domain (amino acids 30-112), which may participate in protein-protein interactions. A centrally positioned SAM domain (amino acids 385-448) is likely involved in oligomerisation or scaffolding functions. The catalytic core of the enzyme resides in the DDHD domain (amino acids 495-700), which confers phospholipase activity. Disordered regions are present at the extreme N-terminus (amino acids 1-24), between the SAM and DDHD domains (amino acids 449-470), and within the DDHD domain itself (amino acids 609-638), potentially providing flexibility for substrate access and conformational changes during catalysis.
Key variants
Pathogenic variants in DDHD2 are typically loss-of-function changes that reduce or eliminate enzyme activity. These include missense variants affecting critical residues within the catalytic DDHD domain, as well as nonsense and frameshift variants that truncate the protein. The majority of reported pathogenic variants are inherited in an autosomal recessive pattern, meaning two altered copies are required to cause disease.
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.1546C>T | p.Arg516Ter | Pathogenic | ★★☆☆ | Hereditary spastic paraplegia 54 |
c.1978G>C | p.Asp660His | Pathogenic/Likely pathogenic | ★★☆☆ | Inborn genetic diseases |
c.344G>A | p.Trp115Ter | Pathogenic | ★★☆☆ | Hereditary spastic paraplegia 54 |
c.371del | p.Lys124fs | Pathogenic/Likely pathogenic | ★★☆☆ | Hereditary spastic paraplegia 54 |
c.420C>A | p.Tyr140Ter | Pathogenic | ★★☆☆ | Hereditary spastic paraplegia 54 |
c.694C>T | p.Arg232Ter | Pathogenic | ★★☆☆ | Hereditary spastic paraplegia 54 |
c.856C>T | p.Gln286Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Hereditary spastic paraplegia 54 |
c.985C>T | p.Arg329Ter | Pathogenic | ★★☆☆ | Hereditary spastic paraplegia 54 |
c.1240_1243del | p.Glu414fs | Pathogenic | ★☆☆☆ | Hereditary spastic paraplegia 54 |
c.819_820del | p.His273fs | Pathogenic | ★☆☆☆ | Hereditary spastic paraplegia 54 |
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
Variants in DDHD2 are associated with a group of neurological conditions characterised by progressive motor dysfunction. Hereditary spastic paraplegia is the most commonly described phenotype, featuring lower limb spasticity, weakness, and difficulty walking. Some individuals also exhibit cerebellar signs such as ataxia, dysarthria, and impaired coordination. The age of onset and severity can vary, with presentations ranging from childhood to adulthood. Intellectual disability has been reported in some cases, though not all affected individuals show cognitive impairment. The underlying mechanism involves disrupted lipid metabolism in neurons, leading to gradual degeneration of specific motor pathways.
No disease links recorded for this gene in our reference set.
UK clinical status
DDHD2 appears on multiple green-rated NHS Genomic Medicine Service panels, reflecting its established clinical relevance in the UK diagnostic pathway. It is included in panels for adult onset hereditary spastic paraplegia (R60), childhood onset hereditary spastic paraplegia (R61), hereditary ataxia with onset in adulthood (R54), and broader panels covering ataxia and cerebellar anomalies, hereditary ataxia, hereditary spastic paraplegia, and intellectual disability (R29). The gene is also listed in the Developmental Disorders Genotype-to-Phenotype (DDG2P) database. Green ratings indicate strong evidence supporting the gene-disease association, and clinicians may request DDHD2 sequencing when a patient's clinical features align with these phenotypes.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What conditions are caused by DDHD2 variants?
Pathogenic variants in DDHD2 are associated with hereditary spastic paraplegia, a condition causing progressive stiffness and weakness in the legs, and cerebellar ataxia, which affects coordination and balance. Some individuals may also have intellectual disability.
How is DDHD2-related spastic paraplegia inherited?
DDHD2-related conditions are typically inherited in an autosomal recessive pattern, meaning an individual must inherit two altered copies of the gene (one from each parent) to develop the condition. Parents who carry one altered copy usually do not show symptoms.
Is DDHD2 tested on the NHS in the UK?
Yes, DDHD2 is included on multiple NHS Genomic Medicine Service panels for hereditary spastic paraplegia, ataxia, and intellectual disability. Clinicians may request testing when a patient's symptoms match these conditions.