CYP2U1

protein-coding

cytochrome P450 family 2 subfamily U member 1, the group of Cytochrome P450 family 2

Gene summary

This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. This enzyme is a hydroxylase that metabolizes arachidonic acid, docosahexaenoic acid, and other long chain fatty acids. [provided by RefSeq, Jul 2008]

Previous symbols:

SPG56

MANE transcript

NM_183075.3

Inheritance

ClinVar variants

P:60U:173B:97

Top phenotype

Spastic paraplegia 56, autosomal recessive with or without pseudoxanthoma elasticum

gnomAD constraint

pLI —, LoF o/e 0.41

Max pathogenic AF

—

Genomic locus

chr4:107,931,549-107,953,461

External References & Databases

Ensembl (ENSG00000155016)

Transcript & Mutation Effects

hg38 • Region Span ~21.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hereditary spastic paraplegia 56STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014015

Submitter: Labcorp Genetics (formerly Invitae)

hereditary spastic paraplegia 56DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014015

Submitter: G2P

hereditary spastic paraplegia 56SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014015

Submitter: Orphanet

hereditary spastic paraplegiaDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019064

Submitter: ClinGen

CYP2U1 was first reported in relation to autosomal recessive hereditary spastic paraplegia (HSP) in 2012 (Tesson et al., PMID: 23176821). HSP (also referred to as familial spastic paraparesis), refers to a group of inherited disorders that are characterised by progressive weakness and spasticity of the lower limbs. Symptoms typically progress slowly and can sometimes present as a static clinical course. Age of onset is variable. HSP can co-occur with other conditions, including epilepsy, cognitive deficits, peripheral neuropathy, impaired vision, and deafness. Twenty-four variants (missense, in-frame indel, nonsense, and frameshift) have been reported in 25 probands in 15 publications. We have included 9 probands and 12 variants in this curation (PMIDs: 23176821, 26914923, 24337409, 290354544, 28725025). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) had been reached (additional PMIDs include: 27679996, 26936192, 27292318, 28120039, 31281085, 31359954, 32006740, 32036589, 34316314, 33107650). Putative loss of function variants account for nearly 50% of observed variants (11/24), but missense variants have also been reported. Functional evidence including protein expression and enzymatic activity studies have been carried out for nine of the 24 variants, supporting the assumption that these variants act through a loss of protein/enzymatic activity. Of note, vision impairment or other eye phenotypes were also observed in 11 of the 24 probands/families. A case study in 2021 (El Matri et al., PMID: 34828401) reported on an individual (aged 12) with p.Arg390* variant in CYP2U1, who presented with macular telangiectasia in the absence of an HSP phenotype. The GCEP did not include this proband in the curation; however, would like to point out that other individuals with the same variant (p.Arg390*) all presented with eye phenotypes and adult-onset HSP phenotypes. This may explain the absence of the phenotype in the individual reported by El Mitri (2021). This gene-disease relationship is modestly supported by a CYP2U1 knockout murine model (PMID: 34546337). However, this knockout model does not recapitulate a locomotor phenotype, only a progressive short term memory loss (Y-maze) and photoreceptor cone degeneration (macular degeneration). In summary, there is definitive evidence to support the relationship between CYP2UI and autosomal recessive HSP. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Cerebral Palsy Gene Curation Expert Panel on October 6, 2022 (SOP Version 9). .

Clinical Genomic Database (CGD)

Spastic paraplegia 56, autosomal recessive with or without pseudoxanthoma elasticumAR

Manifestation: Dermatologic; 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

Refs: 23176821; 33107650

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CYP2U1 variants in ClinVar

16 Conditions Cataloged

Spastic paraplegiaTotal: 220

Inborn genetic diseasesTotal: 83

not providedTotal: 78

Hereditary spastic paraplegia 56Total: 52

Hereditary spastic paraplegiaTotal: 27

CYP2U1-related disorderTotal: 13

not specifiedTotal: 11

See casesTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_183075.3. 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			2 clinvar	78 clinvar		80
missense	6 clinvar	12 clinvar	167 clinvar	17 clinvar	2 clinvar	204
nonsense	5 clinvar	5 clinvar	1 clinvar			11
start loss	1 clinvar	1 clinvar				2
frameshift	17 clinvar	11 clinvar	2 clinvar			30
splice donor/acceptor (+/-2bp)	1 clinvar	1 clinvar	1 clinvar			3
Total	30	30	173	95	2	330

Highest pathogenic variant AF is 0.00007398351

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 21 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_183075.3	RefSeq	NP_898898.1	5	MANE Select
ENST00000332884.11	Ensembl	ENSP00000333212.6	5	MANE Select
ENST00000508453.1	Ensembl	ENSP00000423667.1	4	Standard
ENST00000508453.2	Ensembl	ENSP00000423667.1	4	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

nicotine degradation III
Arachidonic acid metabolism - Homo sapiens (human)
Etodolac Action Pathway
Ketoprofen Action Pathway
Ibuprofen Action Pathway

Biological Process

organic acid metabolic process
xenobiotic metabolic process
exogenous drug catabolic process
oxidation-reduction process
omega-hydroxylase P450 pathway

Molecular Function

monooxygenase activity
iron ion binding
steroid hydroxylase activity
oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen
heme binding

Cellular Component

cytoplasm
endoplasmic reticulum membrane
integral component of membrane
organelle membrane
intracellular membrane-bounded organelle

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000332884
Coding exons: 5
Length: 22089
Individuals with no LoFs: 125704
Homozygous LoFs: 0
Heterozygous LoFs: 44
Defined: 125748
p: 0.000175

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.994	233	280	0.833	0.0000136	3536
Missense (PolyPhen)		87	108.44	0.80227		1333
Synonymous	0.644	103	112	0.922	0.00000567	1095
Loss of Function	2.39	8	19.3	0.414	0.00000107	214

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00025	0.00025	rare
Latino/Admixed American	0.000087	0.000087	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00077	0.00071	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00019	0.00018	rare
South Asian	0.000066	0.000065	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Catalyzes the hydroxylation of arachidonic acid, docosahexaenoic acid and other long chain fatty acids. May modulate the arachidonic acid signaling pathway and play a role in other fatty acid signaling processes. {ECO:0000269|PubMed:14660610}.;
Disease: DISEASE: Spastic paraplegia 56, autosomal recessive (SPG56) [MIM:615030]: A form of spastic paraplegia, a neurodegenerative disorder characterized by a slow, gradual, progressive weakness and spasticity of the lower limbs. Rate of progression and the severity of symptoms are quite variable. Initial symptoms may include difficulty with balance, weakness and stiffness in the legs, muscle spasms, and dragging the toes when walking. Complicated forms are recognized by additional variable features including spastic quadriparesis, seizures, dementia, amyotrophy, extrapyramidal disturbance, cerebral or cerebellar atrophy, optic atrophy, and peripheral neuropathy, as well as by extra neurological manifestations. In SPG56, upper limbs are often also affected. Some SPG56 patients may have a subclinical axonal neuropathy. {ECO:0000269|PubMed:23176821}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.168

Intolerance Scores

LoFtool: 0.272
RVIS EVS: -0.09
RVIS percentile EVS: 46.92

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.177

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium