UV-sensitive syndrome is an autosomal recessive photosensitivity disorder caused by biallelic loss of transcription-coupled nucleotide excision repair (TC-NER). Affected individuals sunburn easily after minimal exposure, and develop freckling and telangiectasia on sun-exposed skin. They have no neurological abnormality and no established predisposition to skin cancer. The interest of the entry is the contrast rather than the repair defect on its own. Two of the three causal genes, ERCC6 (CSB) and ERCC8 (CSA), are the Cockayne syndrome genes. Cockayne syndrome is a severe segmental progeroid disease with neurodegeneration, cachectic dwarfism and early death, while UV-sensitive syndrome is confined to the skin and compatible with a normal lifespan. The two share a TC-NER defect, so the TC-NER defect cannot be what makes Cockayne syndrome severe. A homozygous null CSB allele has been found in a person with UV-sensitive syndrome and no Cockayne features, which is the sharpest form of the problem: complete absence of the protein does not produce the severe disease. The favoured explanation is that CSA and CSB have further transcriptional, mitochondrial or repair-independent roles whose loss drives Cockayne syndrome, but this is not settled, and the entry records it as an open question rather than asserting it. The third gene, UVSSA, is the informative comparator: it acts in the same pathway, is the most frequently reported UV-sensitive syndrome gene, and has never been reported to cause Cockayne syndrome.
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Conditions with similar clinical presentations that must be differentiated from UV-Sensitive Syndrome:
name: UV-Sensitive Syndrome
creation_date: "2026-09-09T16:56:20Z"
category: Genetic
description: >-
UV-sensitive syndrome is an autosomal recessive photosensitivity disorder
caused by biallelic loss of transcription-coupled nucleotide excision repair
(TC-NER). Affected individuals sunburn easily after minimal exposure, and
develop freckling and telangiectasia on sun-exposed skin. They have no
neurological abnormality and no established predisposition to skin cancer.
The interest of the entry is the contrast rather than the repair defect on its
own. Two of the three causal genes, ERCC6 (CSB) and ERCC8 (CSA), are the
Cockayne syndrome genes. Cockayne syndrome is a severe segmental progeroid
disease with neurodegeneration, cachectic dwarfism and early death, while
UV-sensitive syndrome is confined to the skin and compatible with a normal
lifespan. The two share a TC-NER defect, so the TC-NER defect cannot be what
makes Cockayne syndrome severe. A homozygous null CSB allele has been found in
a person with UV-sensitive syndrome and no Cockayne features, which is the
sharpest form of the problem: complete absence of the protein does not produce
the severe disease. The favoured explanation is that CSA and CSB have further
transcriptional, mitochondrial or repair-independent roles whose loss drives
Cockayne syndrome, but this is not settled, and the entry records it as an
open question rather than asserting it.
The third gene, UVSSA, is the informative comparator: it acts in the same
pathway, is the most frequently reported UV-sensitive syndrome gene, and has
never been reported to cause Cockayne syndrome.
parents:
- DNA Repair Disorder
- Photosensitivity Disorder
synonyms:
- UVSS
- UV-sensitive syndrome
- UV sensitive syndrome
- Ultraviolet-sensitive syndrome
disease_term:
preferred_term: UV-sensitive syndrome
term:
id: MONDO:0015797
label: UV-sensitive syndrome
classifications:
harrisons_chapter:
- classification_value: DERMATOLOGY
evidence:
- reference: PMID:34974577
reference_title: "The molecular genetics of UV-Sensitive syndrome: A rare dermal anomaly."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Ultraviolet-sensitive syndrome is a rare skin disorder characterised by heterogeneous phenotypic spectrum of skin freckling, telangiectasia and acute sunburn."
explanation: >-
The source calls it a skin disorder and lists only cutaneous
features, which places it in Harrison's dermatology Part.
- classification_value: GENETICS_ENVIRONMENT_DISEASE
evidence:
- reference: PMID:15486090
reference_title: Complete absence of Cockayne syndrome group B gene product gives rise to UV-sensitive syndrome but not Cockayne syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "UV-sensitive syndrome (UVsS) is a rare autosomal recessive disorder characterized by photosensitivity and mild freckling but without neurological abnormalities or skin tumors."
explanation: >-
Names it an autosomal recessive disorder, and the disease is
expressed only on ultraviolet exposure, so it sits in the
genetics-and-environment Part as well as dermatology.
notes: >-
mechanistic_category is deliberately left unset. Its enum offers
RASopathy, ciliopathy, laminopathy, collagenopathy, desmosomopathy,
mitochondrial disease, amyloidopathy, tauopathy, synucleinopathy,
intermediate filament disease and proteotoxic disease. None of these is
a DNA repair disorder, and stretching one to fit would assert something
false.
prevalence:
- population: Worldwide (published case literature)
measure_type: CASES_IN_LITERATURE
prevalence_class: ULTRA_RARE
notes: >-
A 2021 narrative review counted 18 patients from nine families of
Japanese, French, Israeli, Iranian and Pakistani ancestry. The same review
also quotes a prevalence of 1:100,000, which is deliberately NOT curated
here as a rate: it is an unsourced estimate with no registry or
population-surveillance support behind it, and the deep-research report
flagged it on the same grounds.
evidence:
- reference: PMID:34974577
reference_title: "The molecular genetics of UV-Sensitive syndrome: A rare dermal anomaly."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "So far, only 18 patients from nine different families (Japanese, French, Israeli, Iranian and Pakistani) have been reported in scientific literature."
explanation: >-
Gives the published case count and the reported ancestries, which is
the basis for the CASES_IN_LITERATURE record and the ultra-rare band.
- reference: PMID:26255937
reference_title: Photosensitive human syndromes.
supports: SUPPORT
evidence_source: OTHER
snippet: >-
UV-sensitive syndrome (UVSS) was first described by Itoh and colleagues [34]. ... Although
it is likely that there are hundreds or thousands of people with UVSS worldwide, their
clinical features are so mild that they may easily elude diagnosis as victims of a genetic
disease. To date, only eight patients have been characterized.
explanation: >-
The review distinguishes eight characterized UV-sensitive syndrome patients from
speculation that hundreds or thousands may be undiagnosed worldwide. It does not provide a
measured population rate or the later case count.
progression:
- phase: Cumulative cutaneous change without systemic progression
notes: >-
Freckling, pigmentary change and telangiectasia accumulate with repeated
exposure, so the skin findings worsen over time while the disease itself
does not progress systemically. Growth, cognition and neurological
examination stay normal and survival is not shortened. This is the axis
on which the disorder separates most sharply from Cockayne syndrome,
where progression is the defining feature, so severity here is governed
by cumulative ultraviolet dose and adherence to photoprotection rather
than by a natural history intrinsic to the disease.
A childhood-onset phase is not curated separately: the research report
describes the sunburn as usually recognised in childhood, but no cached
source states it in a quotable sentence.
evidence:
- reference: PMID:26255937
reference_title: Photosensitive human syndromes.
supports: SUPPORT
evidence_source: OTHER
snippet: "no pathologies other than sunburn and freckles have been associated with UVSS"
explanation: >-
States that nothing beyond the cutaneous findings has been associated
with this disease, which is the substance of the claim that it does
not progress systemically.
mechanistic_hypotheses:
- hypothesis_group_id: csa_csb_repair_independent_functions
hypothesis_label: >-
CSA and CSB carry TC-NER-independent functions whose loss produces
Cockayne syndrome
status: CANONICAL
description: >-
The field's general explanation for why the same two genes give two very
different diseases. Because both disorders share the TC-NER defect, the
severity of Cockayne syndrome is attributed to further roles of CSA and
CSB outside transcription-coupled repair - in transcription itself, in
mitochondrial maintenance, and in handling endogenous rather than
UV-induced damage - which would matter most in long-lived post-mitotic
cells. UV-sensitive syndrome alleles would spare those roles. The
hypothesis is coherent and widely held, but it is stated at the level of
"some other function" rather than a specified one, which is why it
remains a hypothesis here rather than a curated mechanism.
applies_to_subtypes:
- UVSS1
- UVSS2
evidence:
- reference: PMID:22466610
reference_title: Mutations in UVSSA cause UV-sensitive syndrome and impair RNA polymerase IIo processing in transcription-coupled nucleotide-excision repair.
supports: SUPPORT
directness: INDIRECT
evidence_source: IN_VITRO
snippet: "Our findings provide mechanistic insights into the processing of stalled RNA polymerase and explain the different clinical features across these TC-NER–deficient disorders."
explanation: >-
The authors frame their result as explaining the clinical divergence
across this disease family, which is the question this hypothesis
group exists to answer. Graded INDIRECT because the sentence claims
the explanation without stating which function differs.
- hypothesis_group_id: csb_pgbd3_fusion_position
hypothesis_label: >-
Outcome is set by where the CSB truncation falls relative to the PGBD3
insertion
status: EMERGING
description: >-
A specific alternative to the general hypothesis above, and a positional
rather than quantitative one. CSB transcripts can read through into an
inserted PiggyBac-derived element, PGBD3, producing a CSB-PGBD3 fusion
protein. On this account UV-sensitive syndrome alleles carry their
nonsense mutations upstream of that insertion in both copies, so no
fusion is made, while Cockayne alleles are mutated downstream of it or in
exon 1, so a fusion protein is still produced. The two diseases would then
differ by the presence of the fusion rather than by how much intact CSB
survives. Forcing an upstream stop codon recovered mitochondrial membrane
potential in Cockayne cells, which connects the model to the
mitochondrial arm of the general hypothesis.
Marked EMERGING rather than ALTERNATIVE: it rests on one cell-line study
and has not been tested against the full set of reported alleles.
applies_to_subtypes:
- UVSS1
evidence:
- reference: GEO:GSE111989
reference_title: Generation of splice switching oligonucleotides targeting the Cockayne syndrome group B gene product in order to change the diseased cell state
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "How the CSB gene determines a patient’s fate is unknown, but one intriguing point is that in UVSS patient cell, there are nonsense mutations in both alleles at the same position in each upstream region of the PiggyBac transposable element derived 3 (PGBD3) inserted region."
explanation: >-
States both that the determinant is unknown and the positional
observation this hypothesis is built on.
notes: >-
Recorded as a hypothesis group rather than only as prose in the
uvss_vs_cs_severity discussion, so that the two competing explanations for
the same divergence are comparable as records. No causal edge in this
entry opts into either group, because the disagreement is about what
Cockayne syndrome adds, not about any step in this disease's own chain.
inheritance:
- name: Autosomal recessive
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
description: >-
Biallelic germline loss-of-function variants in ERCC6, ERCC8 or UVSSA.
Parental consanguinity is reported in several kindreds.
evidence:
- reference: PMID:34974577
reference_title: "The molecular genetics of UV-Sensitive syndrome: A rare dermal anomaly."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "It usually has an autosomal recessive pattern."
explanation: States the mode of inheritance for the syndrome.
has_subtypes:
- name: UVSS1
display_name: UV-sensitive syndrome 1 (ERCC6/CSB-related)
description: >-
Caused by biallelic ERCC6 variants. ERCC6 encodes CSB, the ATPase that
engages RNA polymerase II stalled at a transcription-blocking lesion. The
same gene causes Cockayne syndrome.
subtype_term:
preferred_term: UV-sensitive syndrome 1
term:
id: MONDO:0010909
label: UV-sensitive syndrome 1
genes:
- preferred_term: ERCC6
term:
id: hgnc:3438
label: ERCC6
evidence:
- reference: PMID:22466610
reference_title: Mutations in UVSSA cause UV-sensitive syndrome and impair RNA polymerase IIo processing in transcription-coupled nucleotide-excision repair.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Three of the seven known UV(S)S cases carry mutations in the Cockayne syndrome genes ERCC8 or ERCC6 (also known as CSA and CSB, respectively)."
explanation: >-
Establishes ERCC6 as one of the genes causing this syndrome, which is
what defines this subtype.
- name: UVSS2
display_name: UV-sensitive syndrome 2 (ERCC8/CSA-related)
description: >-
Caused by biallelic ERCC8 variants. ERCC8 encodes CSA, the substrate
receptor of the CRL4-CSA ubiquitin ligase acting on stalled RNA polymerase
II. The same gene causes Cockayne syndrome.
subtype_term:
preferred_term: UV-sensitive syndrome 2
term:
id: MONDO:0013829
label: UV-sensitive syndrome 2
genes:
- preferred_term: ERCC8
term:
id: hgnc:3439
label: ERCC8
evidence:
- reference: PMID:22466610
reference_title: Mutations in UVSSA cause UV-sensitive syndrome and impair RNA polymerase IIo processing in transcription-coupled nucleotide-excision repair.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Three of the seven known UV(S)S cases carry mutations in the Cockayne syndrome genes ERCC8 or ERCC6 (also known as CSA and CSB, respectively)."
explanation: >-
Establishes ERCC8 as one of the genes causing this syndrome, which is
what defines this subtype.
- name: UVSS3
display_name: UV-sensitive syndrome 3 / UVSS-A (UVSSA-related)
description: >-
Caused by biallelic UVSSA variants, and the most frequently reported form.
UVSSA recruits TFIIH to stalled RNA polymerase II and stabilises the CSB
complex. Unlike ERCC6 and ERCC8 it has not been reported to cause Cockayne
syndrome, which makes it the comparator that separates the TC-NER role of
this pathway from whatever else CSA and CSB do.
subtype_term:
preferred_term: UV-sensitive syndrome 3
term:
id: MONDO:0013834
label: UV-sensitive syndrome 3
genes:
- preferred_term: UVSSA
term:
id: hgnc:29304
label: UVSSA
evidence:
- reference: PMID:22466610
reference_title: Mutations in UVSSA cause UV-sensitive syndrome and impair RNA polymerase IIo processing in transcription-coupled nucleotide-excision repair.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Using exome sequencing, we determine that mutations in the UVSSA gene (formerly known as KIAA1530) cause UV(S)S-A."
explanation: Establishes UVSSA as the gene of the UVSS-A complementation group.
- reference: PMID:22466612
reference_title: Mutations in UVSSA cause UV-sensitive syndrome and destabilize ERCC6 in transcription-coupled DNA repair.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We identify three nonsense and frameshift UVSSA mutations in individuals with UV(S)S-A, indicating that UVSSA is the causative gene for this syndrome."
explanation: >-
Independent confirmation of the same gene assignment, reported
simultaneously by a separate group using chromosome transfer rather
than exome sequencing.
pathophysiology:
- name: Biallelic Loss of a TC-NER Factor
description: >-
Loss-of-function variants in ERCC6, ERCC8 or UVSSA remove one component of
the machinery that resolves RNA polymerase II stalled at a
transcription-blocking lesion. Global-genome nucleotide excision repair is
comparatively preserved, which is what separates this disorder from
xeroderma pigmentosum and is why there is no marked cancer predisposition.
biological_scale: MOLECULAR
biological_processes:
- preferred_term: transcription-coupled nucleotide-excision repair
term:
id: GO:0006283
label: transcription-coupled nucleotide-excision repair
modifier: DECREASED
downstream:
- target: Failure to Process Stalled RNA Polymerase II
causal_link_type: DIRECT
evidence:
- reference: PMID:22466610
reference_title: Mutations in UVSSA cause UV-sensitive syndrome and impair RNA polymerase IIo processing in transcription-coupled nucleotide-excision repair.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "The UVSSA protein interacts with TC-NER machinery and stabilizes the ERCC6 complex; it also facilitates ubiquitination of RNA polymerase IIo stalled at DNA damage sites."
explanation: >-
Ties the gene product directly to the processing of stalled
polymerase, which is the step that fails when it is lost.
evidence:
- reference: PMID:22466610
reference_title: Mutations in UVSSA cause UV-sensitive syndrome and impair RNA polymerase IIo processing in transcription-coupled nucleotide-excision repair.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Despite mild clinical features, cells from individuals with UV(S)S, like Cockayne syndrome cells, are very UV sensitive and are deficient in transcription-coupled nucleotide-excision repair (TC-NER), which removes DNA damage in actively transcribed genes."
explanation: >-
Establishes the TC-NER deficiency as the cellular lesion, and states
in the same sentence that Cockayne cells share it.
- name: Failure to Process Stalled RNA Polymerase II
description: >-
Repair normally proceeds by an ordered handover: CSB binds the stalled
polymerase and recruits CSA, CSA loads UVSSA, ELOF1 positions UVSSA and
the CRL4-CSA ligase so that the polymerase is ubiquitylated and
inactivated, and UVSSA then recruits TFIIH to open the DNA. Losing any one
of CSB, CSA or UVSSA breaks this chain, so the arrested polymerase is
neither inactivated nor cleared and the repair machinery is never
delivered to the lesion.
biological_scale: MOLECULAR
cell_types:
- preferred_term: keratinocyte
term:
id: CL:0000312
label: keratinocyte
downstream:
- target: Persistent Transcription Blockage After UV Exposure
causal_link_type: DIRECT
evidence:
- reference: PMID:38316879
reference_title: Structural basis for RNA polymerase II ubiquitylation and inactivation in transcription-coupled repair.
supports: SUPPORT
directness: INDIRECT
evidence_source: IN_VITRO
snippet: "During transcription-coupled DNA repair (TCR), RNA polymerase II (Pol II) transitions from a transcriptionally active state to an arrested state that allows for removal of DNA lesions."
explanation: >-
States that the polymerase transition is what permits lesion
removal, so failing to make that transition leaves the lesion in
place and transcription blocked. Graded INDIRECT because the
source describes the working pathway rather than the failure.
evidence:
- reference: PMID:32355176
reference_title: "The cooperative action of CSB, CSA, and UVSSA target TFIIH to DNA damage-stalled RNA polymerase II."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Importantly, we find that UVSSA is the key factor that recruits the TFIIH complex in a manner that is stimulated by CSB and CSA."
explanation: >-
Establishes the order of the handover and why all three proteins are
needed for the same step.
- reference: PMID:32355176
reference_title: "The cooperative action of CSB, CSA, and UVSSA target TFIIH to DNA damage-stalled RNA polymerase II."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "We show that TCR is initiated by RNAPIIo-bound CSB, which recruits CSA through a newly identified CSA-interaction motif (CIM)."
explanation: Gives the first two steps of the assembly, CSB then CSA.
- reference: PMID:38316879
reference_title: Structural basis for RNA polymerase II ubiquitylation and inactivation in transcription-coupled repair.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "we found that ELOF1 serves as an adaptor to stably position UVSSA and CRL4CSA on arrested Pol II, leading to ligase neddylation and activation of Pol II ubiquitylation."
explanation: >-
Adds the structural step by which the complex is positioned and the
polymerase ubiquitylated.
- reference: PMID:38316879
reference_title: Structural basis for RNA polymerase II ubiquitylation and inactivation in transcription-coupled repair.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "In the presence of ELOF1, a transcription factor IIS (TFIIS)-like element in UVSSA gets ordered and extends through the Pol II pore, thus preventing reactivation of Pol II by TFIIS."
explanation: >-
Shows UVSSA actively holds the polymerase inactive rather than merely
recruiting repair factors, so its loss has two consequences.
- reference: PMID:22466611
reference_title: UV-sensitive syndrome protein UVSSA recruits USP7 to regulate transcription-coupled repair.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "The UVSSA protein interacts with elongating RNA polymerase II, localizes specifically to UV-induced lesions, resides in chromatin-associated TC-NER complexes and is implicated in stabilizing the TC-NER master organizing protein ERCC6 (also known as CSB) by delivering the deubiquitinating enzyme USP7 to TC-NER complexes."
explanation: >-
The source for the USP7 step this node describes, and for UVSSA
stabilising CSB. Both were asserted here without a citation until
this reference was added.
- reference: PMID:22466612
reference_title: Mutations in UVSSA cause UV-sensitive syndrome and destabilize ERCC6 in transcription-coupled DNA repair.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "The UVSSA protein forms a complex with USP7 (ref. 8), stabilizes ERCC6 and restores the hypophosphorylated form of RNA polymerase II after UV irradiation."
explanation: >-
Independently reports the same USP7 complex and CSB stabilisation, and
adds the polymerase phosphorylation-state readout that the processing
step restores.
- name: Persistent Transcription Blockage After UV Exposure
description: >-
Transcription of the damaged strand does not recover after UV irradiation.
This is the defining cellular phenotype and the basis of the
recovery-of-RNA-synthesis assay, which is abnormal while unscheduled DNA
synthesis (reflecting global-genome repair) stays near normal.
biological_scale: CELLULAR
locations:
- preferred_term: skin of body
term:
id: UBERON:0002097
label: skin of body
biological_processes:
- preferred_term: UV-damage excision repair
term:
id: GO:0070914
label: UV-damage excision repair
modifier: DECREASED
downstream:
- target: UV-Induced Keratinocyte Apoptosis
causal_link_type: DIRECT
evidence:
- reference: PMID:26255937
reference_title: Photosensitive human syndromes.
supports: SUPPORT
evidence_source: OTHER
snippet: "The prevailing explanation is that TCR deficiency results in persistent transcription blockage, leading to cell death by apoptosis, or through the compounded problem of replication fork encounters with the immobilized transcription complexes."
explanation: >-
States this exact causal step, and is explicit that it is the
prevailing explanation rather than a demonstrated one, which is
how the node describes it. Graded OTHER because the source is a
narrative review presenting a field consensus, not primary data.
evidence:
- reference: PMID:15486090
reference_title: Complete absence of Cockayne syndrome group B gene product gives rise to UV-sensitive syndrome but not Cockayne syndrome.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "UVsS cells show UV hypersensitivity and defective transcription-coupled DNA repair of UV damage."
explanation: >-
States the cellular phenotype: UV hypersensitivity with a
transcription-coupled repair defect.
- name: UV-Induced Keratinocyte Apoptosis
description: >-
Sustained transcription arrest in UV-exposed epidermal keratinocytes
triggers stress signalling and cell death, producing the exaggerated
sunburn response. This last step is inferred from the repair biology and
the clinical picture rather than traced directly in patient skin, and is
the weakest link in the chain.
biological_scale: CELLULAR
locations:
- preferred_term: skin epidermis
term:
id: UBERON:0001003
label: skin epidermis
cell_types:
- preferred_term: keratinocyte
term:
id: CL:0000312
label: keratinocyte
- preferred_term: melanocyte
term:
id: CL:0000148
label: melanocyte
downstream:
- target: Cutaneous Photosensitivity
causal_link_type: DIRECT
- target: Freckling
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- target: Telangiectasia
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:26255937
reference_title: Photosensitive human syndromes.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "The responses of UVSS and CS cells to treatment with UV light (254 nm) are identical: defective survival, impaired recovery of RNA synthesis, accumulation of p53 correlated with apoptotic response at low UV doses, and proficient global repair of photoproducts;"
explanation: >-
Reports an apoptotic response with p53 accumulation at low UV doses,
which is the cell-death event this node describes. Note the same
sentence records that UV-sensitive syndrome and Cockayne cells behave
identically, so this step is shared with Cockayne syndrome and is not
what makes the two diseases differ.
phenotypes:
- name: Cutaneous Photosensitivity
category: Dermatological
description: >-
Exaggerated sunburn after minimal sun exposure, usually recognised in
childhood. The core presenting feature.
phenotype_term:
preferred_term: Cutaneous photosensitivity
term:
id: HP:0000992
label: Cutaneous photosensitivity
located_in:
preferred_term: skin of body
term:
id: UBERON:0002097
label: skin of body
evidence:
- reference: PMID:15486090
reference_title: Complete absence of Cockayne syndrome group B gene product gives rise to UV-sensitive syndrome but not Cockayne syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "UV-sensitive syndrome (UVsS) is a rare autosomal recessive disorder characterized by photosensitivity and mild freckling but without neurological abnormalities or skin tumors."
explanation: >-
Names photosensitivity as a defining feature, and in the same sentence
excludes neurological disease and skin tumours.
- name: Freckling
category: Dermatological
description: >-
Freckling and pigmentary change on sun-exposed skin, accumulating with
repeated exposure.
phenotype_term:
preferred_term: Freckling
term:
id: HP:0001480
label: Freckling
located_in:
preferred_term: skin epidermis
term:
id: UBERON:0001003
label: skin epidermis
evidence:
- reference: PMID:34974577
reference_title: "The molecular genetics of UV-Sensitive syndrome: A rare dermal anomaly."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Ultraviolet-sensitive syndrome is a rare skin disorder characterised by heterogeneous phenotypic spectrum of skin freckling, telangiectasia and acute sunburn."
explanation: Lists freckling among the defining cutaneous features.
- name: Telangiectasia
category: Dermatological
description: >-
Small clusters of dilated cutaneous vessels, usually over the cheeks and
nose.
phenotype_term:
preferred_term: Telangiectasia
term:
id: HP:0001009
label: Telangiectasia
located_in:
preferred_term: dermis
term:
id: UBERON:0002067
label: dermis
evidence:
- reference: PMID:34974577
reference_title: "The molecular genetics of UV-Sensitive syndrome: A rare dermal anomaly."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Ultraviolet-sensitive syndrome is a rare skin disorder characterised by heterogeneous phenotypic spectrum of skin freckling, telangiectasia and acute sunburn."
explanation: Lists telangiectasia among the defining cutaneous features.
- name: Dry Skin
category: Dermatological
description: >-
Xerosis of sun-exposed skin. Reported repeatedly in the review literature
but generally as part of the cutaneous picture rather than as a separately
quantified finding.
phenotype_term:
preferred_term: Dry skin
term:
id: HP:0000958
label: Dry skin
located_in:
preferred_term: skin epidermis
term:
id: UBERON:0001003
label: skin epidermis
evidence:
- reference: PMID:26255937
reference_title: Photosensitive human syndromes.
supports: SUPPORT
directness: INDIRECT
evidence_source: OTHER
snippet: "Mutations in genes that code for factors involved in the repair of these photoproducts result in enhanced photosensitivity, manifested as acute sunburn, pigmentation anomalies, dryness and atrophy of the skin, and in some patients, a high incidence of cancer in sun-exposed areas."
explanation: >-
Lists dryness among the cutaneous manifestations of defective
photoproduct repair, the class this disease belongs to. Graded
INDIRECT deliberately: the sentence never names UV-sensitive syndrome,
so the claim follows from class membership rather than from direct
observation. Note the same sentence attributes cancer risk to only
some members of the class, which is consistent with this disease
having none.
environmental:
- name: Ultraviolet radiation exposure
description: >-
Solar and artificial ultraviolet radiation is the obligate trigger. The
genotype creates a repair deficiency that is silent until UV generates
transcription-blocking photoproducts, so exposure controls whether and how
severely the disease manifests without being its cause. Artificial sources
that matter clinically include tanning devices, germicidal lamps and
welding arcs.
exposure_term:
preferred_term: exposure to ultraviolet radiation
term:
id: ECTO:0000006
label: exposure to ultraviolet radiation
influences_mechanisms:
- target: Persistent Transcription Blockage After UV Exposure
environmental_effect: TRIGGERS
causal_link_type: DIRECT
description: >-
UV photoproducts on the transcribed strand are the lesions that arrest
RNA polymerase II. Without exposure there is no transcription-blocking
lesion for the defective repair pathway to fail on.
evidence:
- reference: PMID:15486090
reference_title: Complete absence of Cockayne syndrome group B gene product gives rise to UV-sensitive syndrome but not Cockayne syndrome.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "UVsS cells show UV hypersensitivity and defective transcription-coupled DNA repair of UV damage."
explanation: >-
Ties the cellular defect specifically to UV damage, which is what
makes the exposure the trigger for this node rather than general
background context.
evidence:
- reference: PMID:26255937
reference_title: Photosensitive human syndromes.
supports: SUPPORT
directness: INDIRECT
evidence_source: OTHER
snippet: "We will review current understanding of photosensitivity to short wavelength ultraviolet light (UV) due to genetic defects in particular DNA repair pathways; deficiencies in some are characterized by an extremely high incidence of cancer in sun-exposed tissues, while in others no cancers have been reported."
explanation: >-
Frames the disease class as photosensitivity to short-wavelength UV
arising from DNA repair defects, and distinguishes the members that
carry cancer risk from those that do not. Graded INDIRECT because it
describes the class rather than this disease, and OTHER because it is
a narrative review without primary data.
genetic:
- name: ERCC6
gene_term:
preferred_term: ERCC6
term:
id: hgnc:3438
label: ERCC6
notes: >-
Encodes CSB. Biallelic loss causes UVSS1. The same gene more commonly
causes Cockayne syndrome, and a homozygous null allele has been reported
in UV-sensitive syndrome without Cockayne features.
evidence:
- reference: PMID:15486090
reference_title: Complete absence of Cockayne syndrome group B gene product gives rise to UV-sensitive syndrome but not Cockayne syndrome.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "we sequenced the CSB gene from UVs1KO and detected a homozygous null mutation."
explanation: >-
Identifies a homozygous null CSB allele in a UV-sensitive syndrome
cell line, which is the observation the CS contrast rests on.
- name: ERCC8
gene_term:
preferred_term: ERCC8
term:
id: hgnc:3439
label: ERCC8
notes: >-
Encodes CSA. Biallelic loss causes UVSS2; the same gene causes Cockayne
syndrome type A.
evidence:
- reference: PMID:22466610
reference_title: Mutations in UVSSA cause UV-sensitive syndrome and impair RNA polymerase IIo processing in transcription-coupled nucleotide-excision repair.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Three of the seven known UV(S)S cases carry mutations in the Cockayne syndrome genes ERCC8 or ERCC6 (also known as CSA and CSB, respectively)."
explanation: >-
Attributes a share of cases to the two Cockayne syndrome genes, which
is what makes them shared between the two diseases.
- name: UVSSA
gene_term:
preferred_term: UVSSA
term:
id: hgnc:29304
label: UVSSA
notes: >-
Encodes UVSSA, which recruits TFIIH to stalled RNA polymerase II and
carries a TFIIS-like element that keeps the polymerase inactive. The most
frequently reported gene, and not reported in Cockayne syndrome. A 2024
study also implicates it in transcription-coupled repair of interstrand
crosslinks, which is mechanistically notable but of unproven relevance to
untreated patients.
evidence:
- reference: PMID:22466610
reference_title: Mutations in UVSSA cause UV-sensitive syndrome and impair RNA polymerase IIo processing in transcription-coupled nucleotide-excision repair.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Using exome sequencing, we determine that mutations in the UVSSA gene (formerly known as KIAA1530) cause UV(S)S-A."
explanation: The gene-discovery finding for the UVSS-A complementation group.
- reference: PMID:39383571
reference_title: UVSSA facilitates transcription-coupled repair of DNA interstrand crosslinks.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Inactivation of UVSSA sensitizes human cells to ICL-inducing drugs, and delays ICL repair."
explanation: >-
Extends UVSSA function beyond UV photoproducts to interstrand
crosslinks in human cell lines.
experimental_models:
- name: Patient dermal fibroblast lines
experimental_model_type: PRIMARY_CELL_CULTURE
description: >-
Primary fibroblasts cultured from affected individuals. These are the
systems in which the disease was originally defined: UVs1KO, which carries
the homozygous null CSB allele, and Kps3, which has normal CSB protein and
established that the syndrome is genetically heterogeneous. They reproduce
UV hypersensitivity and the recovery-of-RNA-synthesis defect with
relatively preserved unscheduled DNA synthesis, and they support
complementation testing.
organism:
preferred_term: human
term:
id: NCBITaxon:9606
label: Homo sapiens
cell_types:
- preferred_term: dermal fibroblast
term:
id: CL:0000057
label: fibroblast
publication: PMID:15486090
modeled_mechanisms:
- target: Persistent Transcription Blockage After UV Exposure
relationship: RECAPITULATES
fidelity: HIGH
model_scale: CELLULAR
description: >-
The cellular phenotype these lines display is the node itself:
transcription fails to recover after UV while global-genome repair
stays near normal.
limitations: >-
Cultured fibroblasts carry neither the epidermal architecture in which
the disease is expressed nor a lifetime of intermittent solar
exposure, and the assays use acute high-dose 254 nm UV rather than
sunlight.
evidence:
- reference: PMID:15486090
reference_title: Complete absence of Cockayne syndrome group B gene product gives rise to UV-sensitive syndrome but not Cockayne syndrome.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "UVsS cells show UV hypersensitivity and defective transcription-coupled DNA repair of UV damage."
explanation: >-
States the phenotype these patient lines display, which is what
makes them informative for this node.
evidence:
- reference: PMID:15486090
reference_title: Complete absence of Cockayne syndrome group B gene product gives rise to UV-sensitive syndrome but not Cockayne syndrome.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "On the other hand, no mutation in the CSB cDNA and a normal amount of CSB protein was detected in Kps3, a UVsS cell line obtained from an unrelated patient, indicating genetic heterogeneity in UVsS."
explanation: >-
Names one of the patient lines and reports the result that established
genetic heterogeneity, showing what these models were used to decide.
- name: Isogenic TC-NER knockout human cell lines
experimental_model_type: CELL_LINE
description: >-
Human cell lines in which UVSSA, ERCC8 or ERCC6 has been knocked out on a
common genetic background, with rescue by wild-type or mutant protein.
These are the systems that resolved the order of the repair handover and
allow separation of one protein's contribution from another's.
organism:
preferred_term: human
term:
id: NCBITaxon:9606
label: Homo sapiens
publication: PMID:32355176
modeled_mechanisms:
- target: Failure to Process Stalled RNA Polymerase II
relationship: PERTURBS
fidelity: MODERATE
model_scale: MOLECULAR
description: >-
Deleting each factor in turn is what established that CSB acts first,
then CSA, then UVSSA, and that UVSSA is the one that brings in TFIIH.
limitations: >-
Transformed cell lines exposed to acute experimental UV doses, so they
model the molecular handover rather than the disease. A knockout is
also not the same lesion as most patient alleles, which are missense
or truncating variants with residual protein.
evidence:
- reference: PMID:32355176
reference_title: "The cooperative action of CSB, CSA, and UVSSA target TFIIH to DNA damage-stalled RNA polymerase II."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Here, we define the assembly mechanism of the TCR complex in human isogenic knockout cells."
explanation: >-
Names the model system and the question it was used to answer,
which is the assembly step this node describes.
evidence:
- reference: PMID:38316879
reference_title: Structural basis for RNA polymerase II ubiquitylation and inactivation in transcription-coupled repair.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "This transition requires site-specific ubiquitylation of Pol II by the CRL4CSA ubiquitin ligase, a process that is facilitated by ELOF1 in an unknown way."
explanation: >-
States the molecular step these engineered systems were built to
dissect, and is explicit that part of it was unresolved.
diagnosis:
- name: Recovery of RNA synthesis assay in patient fibroblasts
description: >-
The functional test that defines the disorder. After UV irradiation,
patient fibroblasts fail to restore RNA synthesis while unscheduled DNA
synthesis, which reflects global-genome repair, remains near normal. That
combination separates this disorder from xeroderma pigmentosum, in which
global-genome repair is the defective arm. It does not separate it from
Cockayne syndrome, which gives the same cellular result.
evidence:
- reference: PMID:22466610
reference_title: Mutations in UVSSA cause UV-sensitive syndrome and impair RNA polymerase IIo processing in transcription-coupled nucleotide-excision repair.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Despite mild clinical features, cells from individuals with UV(S)S, like Cockayne syndrome cells, are very UV sensitive and are deficient in transcription-coupled nucleotide-excision repair (TC-NER), which removes DNA damage in actively transcribed genes."
explanation: >-
Establishes the cellular signature the assay detects, and says in the
same sentence that Cockayne cells give the same result, which is why
the assay cannot discriminate between them.
notes: >-
Specialised and not standardised across routine laboratories, with no
universal clinical cutoffs, so molecular confirmation of biallelic
variants is the practical diagnostic endpoint.
- name: Molecular genetic testing
description: >-
A hereditary photosensitivity or DNA-repair gene panel covering at minimum
UVSSA, ERCC8 and ERCC6, preferably alongside the xeroderma pigmentosum,
Cockayne and trichothiodystrophy genes given the phenotypic overlap.
Exome sequencing is the appropriate next step when a panel is negative.
diagnosis_term:
preferred_term: Genetic Testing
term:
id: NCIT:C15709
label: Genetic Testing
evidence:
- reference: PMID:22466610
reference_title: Mutations in UVSSA cause UV-sensitive syndrome and impair RNA polymerase IIo processing in transcription-coupled nucleotide-excision repair.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Using exome sequencing, we determine that mutations in the UVSSA gene (formerly known as KIAA1530) cause UV(S)S-A."
explanation: >-
Exome sequencing is what identified the third gene, and is the method
that resolves cases a targeted panel misses.
variants:
- name: ERCC6 c.229C>T (p.Arg77X)
description: >-
Homozygous nonsense allele reported in two individuals with UV-sensitive
syndrome, truncating CSB near the N-terminus and so amounting to a null.
This is the allele behind the entry's central contrast: a null at ERCC6
that produces the mild disease rather than Cockayne syndrome.
gene:
preferred_term: ERCC6
term:
id: hgnc:3438
label: ERCC6
clinical_significance: PATHOGENIC
evidence:
- reference: PMID:22466610
reference_title: Mutations in UVSSA cause UV-sensitive syndrome and impair RNA polymerase IIo processing in transcription-coupled nucleotide-excision repair.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Two UVSS cases (UVS1KO, CS3AM) carried the same homozygous termination mutation in the ERCC6 gene (c.229C>T), which causes a severe truncation near the N-terminus of the 140 kDa ERCC6 (CSB) protein (p.Arg77X)"
explanation: >-
Names the allele, its zygosity, the two cases carrying it and its
protein consequence in one sentence. The same sentence goes on to
note that other ERCC6 mutations cause the much more severe Cockayne
phenotype, which is the contrast this entry is built around.
- name: ERCC8 c.1083G>T (p.Trp361Cys)
description: >-
Homozygous missense allele near the C-terminus of CSA, reported in one
individual with UV-sensitive syndrome. Treated as loss of function on the
basis that it causes the recessive phenotype; the cited text describes the
substitution rather than a functional assay.
gene:
preferred_term: ERCC8
term:
id: hgnc:3439
label: ERCC8
clinical_significance: PATHOGENIC
evidence:
- reference: PMID:22466610
reference_title: Mutations in UVSSA cause UV-sensitive syndrome and impair RNA polymerase IIo processing in transcription-coupled nucleotide-excision repair.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Another case (UVSS1VI) carried a homozygous mutation in the ERCC8 gene (c.1083G>T), causing a missense change close to the C-terminus of the 40kDa ERCC8 (CSA) protein"
explanation: >-
Names the allele, its zygosity, the case carrying it and its protein
consequence.
- name: UVSSA nonsense and frameshift alleles
description: >-
The UVSSA alleles reported in the original description are nonsense and
frameshift changes. Curated deliberately as an allelic class rather than
as individual variants, because the specific HGVS strings could not be
verified against a quotable patient-level statement; the reasons are in
this entry's notes.
gene:
preferred_term: UVSSA
term:
id: hgnc:29304
label: UVSSA
clinical_significance: PATHOGENIC
evidence:
- reference: PMID:22466612
reference_title: Mutations in UVSSA cause UV-sensitive syndrome and destabilize ERCC6 in transcription-coupled DNA repair.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We identify three nonsense and frameshift UVSSA mutations in individuals with UV(S)S-A, indicating that UVSSA is the causative gene for this syndrome."
explanation: >-
States the allele class found in patients and that it establishes
causation, without committing this record to a specific HGVS string.
treatments:
- name: Photoprotection
description: >-
Management is entirely preventive. Sun avoidance, broad-spectrum
sunscreen, protective clothing and gloves, sunglasses, and emollients for
dry skin. These reduce the lesion burden rather than correcting the repair
defect, and no disease-modifying therapy exists.
therapeutic_modality: BEHAVIORAL
treatment_term:
preferred_term: photoprotection and ultraviolet avoidance
term:
id: NCIT:C15747
label: Supportive Care
therapeutic_agent:
- preferred_term: sunscreen
term:
id: NCIT:C851
label: Sunscreen
target_phenotypes:
- preferred_term: Cutaneous photosensitivity
term:
id: HP:0000992
label: Cutaneous photosensitivity
evidence:
- reference: PMID:34974577
reference_title: "The molecular genetics of UV-Sensitive syndrome: A rare dermal anomaly."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "In order to reduce the disease severity, the patients are advised to use medicated skin moisturisers or sun-blocks, sunglasses and gloves, while going out in the sun to avoid sun exposure."
explanation: >-
States the photoprotective measures recommended, which is the whole of
current management.
notes: >-
Bound to the generic Supportive Care action because NCIT has no
clinical-action term for sun avoidance; the specificity is carried in
preferred_term. NCIT:C851 Sunscreen is a substance rather than an action
and so sits in therapeutic_agent, following the device/agent pattern in
CLAUDE.md.
differential_diagnoses:
- name: Cockayne Syndrome
disease_term:
preferred_term: Cockayne syndrome
term:
id: MONDO:0016006
label: Cockayne syndrome
description: >-
Shares the TC-NER defect and two of the three causal genes, but adds
progressive neurodegeneration, cachectic dwarfism, developmental failure
and premature ageing. The distinction is clinical, not biochemical: both
disorders fail the recovery-of-RNA-synthesis assay.
distinguishing_features:
- >-
Absence of neurological, growth and developmental abnormality in
UV-sensitive syndrome.
- >-
A homozygous null CSB allele has been observed in UV-sensitive syndrome
without Cockayne features, so genotype at ERCC6 alone does not separate
the two disorders.
evidence:
- reference: PMID:15486090
reference_title: Complete absence of Cockayne syndrome group B gene product gives rise to UV-sensitive syndrome but not Cockayne syndrome.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "This finding was surprising because a null mutation of the CSB gene would be expected to result in CS features such as severe developmental and neurological abnormalities."
explanation: >-
States the genotype-phenotype discrepancy in the authors' own words:
a CSB null did not produce Cockayne syndrome.
- reference: PMID:20301516
reference_title: "Cockayne Syndrome."
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: "Progressive impairment of vision, hearing, and central and peripheral nervous system function leads to severe disability; death typically occurs in the first or second decade."
explanation: >-
Substantiates the Cockayne side of the contrast: the neurological
deterioration and shortened lifespan that UV-sensitive syndrome
lacks. Graded INDIRECT because the source never mentions
UV-sensitive syndrome, so it establishes only what the comparator
disorder looks like, not the absence of those features here.
discussions:
- discussion_id: uvss_vs_cs_severity
kind: KNOWLEDGE_GAP
status: OPEN
prompt: >-
Why does loss of CSA or CSB cause Cockayne syndrome in most people but
UV-sensitive syndrome in others, when both disorders share the same
transcription-coupled repair defect?
attaches_to:
- pathophysiology#Failure to Process Stalled RNA Polymerase II
rationale: >-
The TC-NER defect is common to both disorders, so it cannot by itself
explain why one is a fatal multisystem progeroid disease and the other is
confined to the skin. A homozygous null CSB allele has been reported in
UV-sensitive syndrome without Cockayne features, which rules out simple
dose of residual CSB activity as the answer. The favoured explanation is
that CSA and CSB carry further transcriptional, mitochondrial or
repair-independent functions whose loss produces the Cockayne phenotype,
and that these are somehow spared in UV-sensitive syndrome. That remains
an inference. UVSSA is the natural comparator, since it acts in the same
pathway and has never been reported to cause Cockayne syndrome.
One concrete candidate mechanism is on the table, and it is positional
rather than quantitative. CSB transcripts can read through into an
inserted PiggyBac-derived element, PGBD3, producing a CSB-PGBD3 fusion
protein. A dataset curated here (geo:GSE111989) reports that
UV-sensitive syndrome alleles carry their nonsense mutations upstream of
that insertion in both copies, while Cockayne alleles are mutated
downstream of it or in exon 1 - so the two diseases would differ by
whether the fusion protein can still be made, not by how much CSB
survives. The same work reports that forcing an upstream stop codon
recovered mitochondrial membrane potential in Cockayne cells, which is
the kind of repair-independent function the general explanation appeals
to. This is a hypothesis supported by a cell-line experiment, not an
established mechanism, and it has not been tested against the full set of
reported alleles.
evidence:
- reference: PMID:15486090
reference_title: Complete absence of Cockayne syndrome group B gene product gives rise to UV-sensitive syndrome but not Cockayne syndrome.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "This finding was surprising because a null mutation of the CSB gene would be expected to result in CS features such as severe developmental and neurological abnormalities."
explanation: >-
The authors themselves frame the observation as an unexplained
genotype-phenotype discrepancy, which is what this gap records.
- reference: PMID:22466610
reference_title: Mutations in UVSSA cause UV-sensitive syndrome and impair RNA polymerase IIo processing in transcription-coupled nucleotide-excision repair.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Despite mild clinical features, cells from individuals with UV(S)S, like Cockayne syndrome cells, are very UV sensitive and are deficient in transcription-coupled nucleotide-excision repair (TC-NER), which removes DNA damage in actively transcribed genes."
explanation: >-
Confirms the shared cellular defect that makes the clinical divergence
a genuine puzzle rather than a difference in repair capacity.
- reference: GEO:GSE111989
reference_title: Generation of splice switching oligonucleotides targeting the Cockayne syndrome group B gene product in order to change the diseased cell state
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "How the CSB gene determines a patient’s fate is unknown, but one intriguing point is that in UVSS patient cell, there are nonsense mutations in both alleles at the same position in each upstream region of the PiggyBac transposable element derived 3 (PGBD3) inserted region."
explanation: >-
States both that the determinant of outcome is unknown and the
positional observation about the PGBD3 insertion that is the leading
candidate explanation, which is what the rationale now records.
datasets:
- accession: geo:GSE132840
title: eXcision Repair-sequencing (XR-seq) to map UV induced damage in U2OS cells and in U2OS cells in which CSA or UVSSA genes were knocked out
description: >-
Genome-wide maps of UV-damage excision repair in wild-type human cells and
in CSA- and UVSSA-knockout cells, with complementation by wild-type and
mutant UVSSA. Measures the repair step this entry's mechanism nodes
describe, in the same isogenic knockout system curated under
experimental_models.
data_type: BULK_RNA_SEQ
organism:
preferred_term: human
term:
id: NCBITaxon:9606
label: Homo sapiens
sample_count: 9
publication: PMID:32355176
genes:
- preferred_term: UVSSA
term:
id: hgnc:29304
label: UVSSA
- preferred_term: ERCC8
term:
id: hgnc:3439
label: ERCC8
evidence:
- reference: GEO:GSE132840
reference_title: eXcision Repair-sequencing (XR-seq) to map UV induced damage in U2OS cells and in U2OS cells in which CSA or UVSSA genes were knocked out
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Complementation of UVSSA knockout with WT or mutant proteins shows UVSSA is a core component of human transcription coupled repair."
explanation: >-
The repository's own summary states what the experiment established,
which is the UVSSA role this entry's mechanism nodes assert.
notes: >-
The most directly on-topic of the four candidates returned by
just discover-datasets: it perturbs two of the three causal genes and
measures the repair step itself, and its linked publication
(PMID:32355176) is already cited here.
- accession: geo:GSE111989
title: Generation of splice switching oligonucleotides targeting the Cockayne syndrome group B gene product in order to change the diseased cell state
description: >-
Splice-switching oligonucleotides designed to skip CSB exon 3, framed
explicitly around why the same gene gives Cockayne syndrome in some people
and UV-sensitive syndrome in others. The stated observation is positional:
in UV-sensitive syndrome cells the nonsense mutations sit upstream of the
PGBD3 insertion in both alleles, whereas Cockayne cells carry mutations
downstream of it or in exon 1. Forcing an upstream stop codon recovered
mitochondrial membrane potential in Cockayne cells.
data_type: MICROARRAY
organism:
preferred_term: human
term:
id: NCBITaxon:9606
label: Homo sapiens
sample_count: 16
genes:
- preferred_term: ERCC6
term:
id: hgnc:3438
label: ERCC6
evidence:
- reference: GEO:GSE111989
reference_title: Generation of splice switching oligonucleotides targeting the Cockayne syndrome group B gene product in order to change the diseased cell state
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "The Cockayne syndrome group B (CSB) gene is one gene responsible for CS and also causes UV sensitive syndrome (UVSS), a disorder that causes mild symptoms."
explanation: >-
States the shared-gene, divergent-outcome relationship that this
entry's knowledge gap is about, from a dataset that was designed
around it.
notes: >-
Bears directly on the uvss_vs_cs_severity knowledge gap and is the reason
that discussion now names the CSB-PGBD3 hypothesis. No linked PubMed
record was found for this series.
- accession: geo:GSE121960
title: Survival of cells with deregulated MYC requires UVSSA-dependent regulation of RNAPII dynamics
description: >-
UVSSA knockdown in MYC-activated cancer cells, measuring RNA polymerase II
dynamics. The disease framing is oncology, not this syndrome, but the
biology measured is UVSSA-dependent handling of RNA polymerase II, which
is the mechanism node this entry is built on.
data_type: CHIP_SEQ
organism:
preferred_term: human
term:
id: NCBITaxon:9606
label: Homo sapiens
sample_count: 16
publication: PMID:33404608
genes:
- preferred_term: UVSSA
term:
id: hgnc:29304
label: UVSSA
evidence:
- reference: GEO:GSE121960
reference_title: Survival of cells with deregulated MYC requires UVSSA-dependent regulation of RNAPII dynamics
supports: SUPPORT
directness: INDIRECT
evidence_source: IN_VITRO
snippet: "Based on previously conducted genome-wide screenings we identified UVSSA, a gene involved in transcription-coupled repair whose knockdown decreased cell viability when combined with MYC activation."
explanation: >-
Confirms the gene identity and its transcription-coupled repair role.
Graded INDIRECT because the experiment is about oncogene-driven
transcription stress rather than this disease.
notes: >-
Included as a gene-matched resource under one of the three causal genes,
with the caveat stated: it measures the pathway, not the syndrome. A
curator reading it for disease phenotype rather than for UVSSA-RNAPII
biology would be misreading it.
- accession: geo:GSE168861
title: Transcriptional analysis of nucleotide excision repair defects
description: >-
shRNA depletion of nucleotide excision repair genes in MCF-10A cells, with
transcriptional readout. Covers the repair pathway broadly rather than
this disease specifically; matched here on ERCC6.
data_type: BULK_RNA_SEQ
organism:
preferred_term: human
term:
id: NCBITaxon:9606
label: Homo sapiens
sample_count: 18
publication: PMID:34066883
genes:
- preferred_term: ERCC6
term:
id: hgnc:3438
label: ERCC6
evidence:
- reference: GEO:GSE168861
reference_title: Transcriptional analysis of nucleotide excision repair defects
supports: SUPPORT
directness: INDIRECT
evidence_source: IN_VITRO
snippet: "Human mammary MCF-10A cells with shRNA-mediated depletion of genes involved in NER"
explanation: >-
Describes the system: NER-gene depletion in a human cell line. Graded
INDIRECT because it addresses the repair pathway generally rather than
this syndrome.
notes: >-
Gene-matched on ERCC6 and pathway-relevant, but neither disease-specific
nor restricted to transcription-coupled repair. Knockdown in a breast
epithelial line is also not the keratinocyte context of the disease.
notes: >-
Curated from a Falcon (Edison) deep-research report,
research/UV-Sensitive_Syndrome-deep-research-falcon.md. The report resolved
9/9 references and 16/16 ontology terms with no unresolved identifiers and no
off-topic references; its one flagged label was the template's own
"(if available)" boilerplate being parsed as a label for MONDO:0015797, not a
report defect. The Named Entity Confusion preflight returned SKIP rather than
PASS, because MONDO records no causal gene for MONDO:0015797, so disease
identity was confirmed manually instead: MONDO:0015797 carries
xref OMIMPS:600630, matching the OMIM number the report gives, and the
report's gene profile (UVSSA, ERCC6, ERCC8) matches MONDO's own subtype terms.
Every ontology CURIE here was resolved by lookup while it was written
(ols:mondo, ols:hp, ols:go, ols:cl, ols:ncit; HGNC from cache/hgnc/terms.csv
and sqlite:obo:hgnc).
No individual UVSSA allele is curated under variants, on purpose. The
deep-research report offered c.367A>T (p.Lys123Ter) among others, but in the
cached full text of PMID:22466610 the only sentence carrying c.367A>T
describes it as a heterozygous variant in a Japanese control individual, not
a patient allele; the patient-level form appears only as a table fragment
("p.Lys123* (Hom)") that cannot be quoted as a proposition. The report also
flags that secondary sources disagree over p.Trp347Ter versus p.Tyr347Ter for
another allele, and that cDNA numbering is inconsistent between sources.
Curating specific UVSSA HGVS strings needs transcript-level verification
against the primary tables and is a separate job from this entry.
mappings: is absent because the schema has nowhere to put what MONDO actually
records here. DiseaseMappings supports only icd10cm, icd11f, mondo and ncit
mappings, while MONDO:0015797's cross-references are DOID, GARD, ICD9,
MEDGEN, MESH, OMIMPS, Orphanet, SCTID and UMLS. There is no ICD10CM, ICD11 or
NCIT xref on the parent term to record, so the section would be empty rather
than merely unwritten.
Deliberate omissions. The 1:100,000 prevalence figure is recorded in
the prevalence notes as unsupported rather than curated as a rate. Li et al.
2019 (PMID:30182135, two novel ERCC8 variants) is cited by the research report,
but just fetch-reference returns a publisher "File not found" page for it
rather than an abstract, so no snippet can be taken from it. It carries no
evidence item and its cache file is deliberately not committed, since nothing
cites it. Re-fetch it before relying on this note; the publisher may have
fixed the record. ELOF1 appears in the mechanism
as a pathway factor and is not a disease gene.
There is no TC-NER mechanism module in kb/modules/, so no conforms_to link is
declared. Such a module would have several conformers (Cockayne syndrome,
COFS, trichothiodystrophy, xeroderma pigmentosum, this entry). Note this has
been considered before and declined: COFS_Syndrome.yaml states that it mirrors
the shared TC-NER biology "rather than inherited via `conforms_to` because
dismech modules are reserved for cross-disorder conserved mechanisms". That
reasoning is worth revisiting now that five entries share the pathway, but it
should be revisited deliberately rather than quietly reversed here.
UVSSA was reported by three simultaneous 2012 Nature Genetics papers, and all
three are cited: Nakazawa (PMID:22466610, exome sequencing), Zhang
(PMID:22466612, chromosome transfer) and Schwertman (PMID:22466611, the
UVSSA-USP7 interaction). The first pass cited only Nakazawa, which left the
USP7 step and the CSB-stabilisation claim asserted without a source.
Three causal edges are deliberately left uncited: the ones running from
UV-Induced Keratinocyte Apoptosis to the three cutaneous phenotypes. The
sources establish that the cells die and that patients develop these signs,
but none states that the one produces the other in skin. The research report
says the same thing, calling the tissue-level link "biologically well
supported but inferred from repair and clinical data rather than directly
traced in patients". Citing a node's evidence on those edges would assert
something no source says, so they stay empty and the node description records
the weakness.
mechanistic_category is unset because its enum has no DNA repair value; the
reason is recorded on the classifications block rather than only here.
Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.
Record notes
Curated from a Falcon (Edison) deep-research report, research/UV-Sensitive_Syndrome-deep-research-falcon.md. The report resolved 9/9 references and 16/16 ontology terms with no unresolved identifiers and no off-topic references; its one flagged label was the template's own "(if available)" boilerplate being parsed as a label for MONDO:0015797, not a report defect. The Named Entity Confusion preflight returned SKIP rather than PASS, because MONDO records no causal gene for MONDO:0015797, so disease identity was confirmed manually instead: MONDO:0015797 carries xref OMIMPS:600630, matching the OMIM number the report gives, and the report's gene profile (UVSSA, ERCC6, ERCC8) matches MONDO's own subtype terms. Every ontology CURIE here was resolved by lookup while it was written (ols:mondo, ols:hp, ols:go, ols:cl, ols:ncit; HGNC from cache/hgnc/terms.csv and sqlite:obo:hgnc). No individual UVSSA allele is curated under variants, on purpose. The deep-research report offered c.367A>T (p.Lys123Ter) among others, but in the cached full text of PMID:22466610 the only sentence carrying c.367A>T describes it as a heterozygous variant in a Japanese control individual, not a patient allele; the patient-level form appears only as a table fragment ("p.Lys123* (Hom)") that cannot be quoted as a proposition. The report also flags that secondary sources disagree over p.Trp347Ter versus p.Tyr347Ter for another allele, and that cDNA numbering is inconsistent between sources. Curating specific UVSSA HGVS strings needs transcript-level verification against the primary tables and is a separate job from this entry. mappings: is absent because the schema has nowhere to put what MONDO actually records here. DiseaseMappings supports only icd10cm, icd11f, mondo and ncit mappings, while MONDO:0015797's cross-references are DOID, GARD, ICD9, MEDGEN, MESH, OMIMPS, Orphanet, SCTID and UMLS. There is no ICD10CM, ICD11 or NCIT xref on the parent term to record, so the section would be empty rather than merely unwritten. Deliberate omissions. The 1:100,000 prevalence figure is recorded in the prevalence notes as unsupported rather than curated as a rate. Li et al. 2019 (PMID:30182135, two novel ERCC8 variants) is cited by the research report, but just fetch-reference returns a publisher "File not found" page for it rather than an abstract, so no snippet can be taken from it. It carries no evidence item and its cache file is deliberately not committed, since nothing cites it. Re-fetch it before relying on this note; the publisher may have fixed the record. ELOF1 appears in the mechanism as a pathway factor and is not a disease gene. There is no TC-NER mechanism module in kb/modules/, so no conforms_to link is declared. Such a module would have several conformers (Cockayne syndrome, COFS, trichothiodystrophy, xeroderma pigmentosum, this entry). Note this has been considered before and declined: COFS_Syndrome.yaml states that it mirrors the shared TC-NER biology "rather than inherited via `conforms_to` because dismech modules are reserved for cross-disorder conserved mechanisms". That reasoning is worth revisiting now that five entries share the pathway, but it should be revisited deliberately rather than quietly reversed here. UVSSA was reported by three simultaneous 2012 Nature Genetics papers, and all three are cited: Nakazawa (PMID:22466610, exome sequencing), Zhang (PMID:22466612, chromosome transfer) and Schwertman (PMID:22466611, the UVSSA-USP7 interaction). The first pass cited only Nakazawa, which left the USP7 step and the CSB-stabilisation claim asserted without a source. Three causal edges are deliberately left uncited: the ones running from UV-Induced Keratinocyte Apoptosis to the three cutaneous phenotypes. The sources establish that the cells die and that patients develop these signs, but none states that the one produces the other in skin. The research report says the same thing, calling the tissue-level link "biologically well supported but inferred from repair and clinical data rather than directly traced in patients". Citing a node's evidence on those edges would assert something no source says, so they stay empty and the node description records the weakness. mechanistic_category is unset because its enum has no DNA repair value; the reason is recorded on the classifications block rather than only here.
Add mechanistic_hypotheses, variants and progression · 2026-09-09T20:42:55Z · View source
Fills the remaining curatable sections identified in a completeness review. mechanistic_hypotheses: the two competing explanations for why the same genes give Cockayne syndrome in most people and this disease in others are now first-class records rather than prose inside a discussion rationale. csa_csb_repair_independent_functions (CANONICAL) is the field's general account - CSA/CSB have roles outside TC-NER whose loss drives the severe phenotype - recorded as a hypothesis precisely because it is stated as 'some other function' rather than a specified one. csb_pgbd3_fusion_position (EMERGING) is the specific positional alternative surfaced by geo:GSE111989: whether the CSB truncation falls upstream or downstream of the PGBD3 insertion determines whether a CSB-PGBD3 fusion protein is still made. No causal edge opts into either group, because the disagreement concerns what Cockayne syndrome adds rather than any step in this disease's own chain; that is stated in the group notes rather than left implicit. variants: two alleles curated with exact quotes from the Nakazawa full text - ERCC6 c.229C>T (p.Arg77X), the null that produces the mild disease and so carries the entry's central contrast, and ERCC8 c.1083G>T (p.Trp361Cys). UVSSA is curated as an allelic class, not as individual variants, and the reason is recorded: the deep-research report offered c.367A>T (p.Lys123Ter), but the only cached sentence carrying c.367A>T describes it as a heterozygous variant in a Japanese control individual, not a patient allele, and the patient-level form appears only as a table fragment that cannot be quoted as a proposition. The report separately flags that secondary sources disagree over p.Trp347Ter versus p.Tyr347Ter and that cDNA numbering is inconsistent. Curating specific UVSSA HGVS needs transcript-level verification against primary tables. progression: one phase, not two. A childhood-onset phase was drafted and then dropped because no cached source states the onset quotably; that omission is recorded in the phase notes rather than silently made. The surviving phase is evidenced by a source stating that no pathologies other than sunburn and freckles have been associated with the disease. prevalence gains a second evidence item arguing the published count is an ascertainment floor: the same review holds that hundreds or thousands of people likely have the disease but escape diagnosis because the phenotype is mild. This is the substantive justification for CASES_IN_LITERATURE with no rate attached. mappings: remains absent and this is now explained in the notes rather than looking unwritten. DiseaseMappings supports only icd10cm, icd11f, mondo and ncit mappings, while MONDO:0015797's cross-references are DOID, GARD, ICD9, MEDGEN, MESH, OMIMPS, Orphanet, SCTID and UMLS - none of which the schema can hold. Compliance 97.6% to 97.9% (137/140); snippets 45 to 52, all exact-quote verified. The three remaining unmet checks are the causal edges from UV-Induced Keratinocyte Apoptosis to the three cutaneous phenotypes, unchanged and deliberate.
Create: UV-Sensitive Syndrome (MONDO:0015797) · 2026-09-09T17:35:53Z · View source
New entry for UV-sensitive syndrome, curated from a Falcon (Edison) deep-research run (research/UV-Sensitive_Syndrome-deep-research-falcon.md, 548s, 8 unique sources behind 44 citation strings). Lump/split: curated as ONE entry with three has_subtypes records (UVSS1/ERCC6, UVSS2/ERCC8, UVSS3/UVSSA), following the merged stub-queue decision in PR #9855 which folded the three seeded per-gene stubs into a single DISEASE stub. stubs/UV-sensitive_Syndrome.yaml deleted. Report screening: reference validation 9/9 resolved, 0 unresolved, 0 off-topic (on_topic 3 of 9, the other 6 undecided for lack of abstracts). Term validation 16/16 resolved; the single mislabelled term was MONDO:0015797 reported as 'if available', which is the prompt template's own boilerplate being parsed as a label, not a report defect. just preflight-dr returned SKIP, not PASS, because MONDO records no causal gene (RO:0004003) for MONDO:0015797. Identity was therefore confirmed manually: MONDO:0015797 carries xref OMIMPS:600630 matching the report's OMIM number, and the report's gene profile (UVSSA 47, ERCC6 17, ERCC8 16 mentions) matches MONDO's own subtype terms, with Cockayne syndrome appearing only as the intended contrast. Sources: the report cites by author-year key with no PMIDs anywhere. Eight unique DOIs were recovered from the citation sidecar and resolved to PMIDs via the PMC ID Converter and PubMed [AID] search. PMID:22466610 (UVSSA discovery), PMID:15486090 (the CSB-null contrast), PMID:32355176 (CSB/CSA/UVSSA/TFIIH assembly), PMID:38316879 (ELOF1 structural), PMID:34974577 (clinical review), PMID:39383571 (UVSSA in interstrand-crosslink repair; the published DNA Repair version was used in preference to the bioRxiv preprint PMID:37214867 the report cited). Deliberate omissions, all recorded in the entry notes: the review's 1:100,000 prevalence is not curated as a rate because it has no surveillance basis; xerosis is not curated as a phenotype because no cached source states it quotably; PMID:30182135 (Li 2019) carries no evidence item because its cached record is a publisher 'File not found' page rather than an abstract. No GeneReviews chapter exists for this disease (two PubMed searches returned zero), and the Cockayne GeneReviews chapter PMID:20301516 cannot substitute because its cached abstract does not mention UV-sensitive syndrome. No conforms_to link: there is no TC-NER module in kb/modules/. Flagged in notes as worth creating separately, since it would have several conformers. Validation: just validate, just validate-disorders, count-verified-snippets (21/21 verified), check-entity-refs, check-causal-targets, check-duplicate-keys, check-qualifier-terms, check-enum-values, check-reference-titles, check-title-snippets, check-snippet-grading all pass.
Target disease: UV-sensitive syndrome (UVSS)
Category: rare Mendelian DNA-repair disorder
MONDO: MONDO:0015797
UVSS is an exceptionally rare, usually childhood-recognized, autosomal-recessive photodermatosis caused by biallelic defects in UVSSA, ERCC8/CSA, or ERCC6/CSB. Its defining phenotype is disproportionate sunburn and pigmentary change—especially freckling, xerosis, and sometimes telangiectasia—on sun-exposed skin, without the progressive neurologic, growth, developmental, or progeroid manifestations characteristic of Cockayne syndrome (CS). Patient cells are UV hypersensitive and fail to restore RNA synthesis after UV exposure, while global-genome nucleotide-excision repair remains comparatively intact. This identifies the central lesion as defective transcription-coupled nucleotide-excision repair (TC-NER) rather than generalized NER failure. No convincing UVSS-specific predisposition to skin or internal cancer has been established, but the number and follow-up of reported patients are too small to declare the risk zero. (spivak2015photosensitivehumansyndromes. pages 4-6, muzammal2021themoleculargenetics pages 1-2, li2019twonovelmutations pages 2-2, muzammal2021themoleculargenetics pages 3-5)
A 2021 review counted only 18 patients from nine families and listed Japanese, French, Israeli, Iranian, and Pakistani kindreds. Its quoted prevalence estimate of 1:100,000 is not supported by registry or population-surveillance data and should not be entered as a validated prevalence; incidence, sex ratio, carrier frequency, penetrance, and survival statistics remain unknown. (muzammal2021themoleculargenetics pages 1-2)
The following table summarizes the strongest evidence and its limitations.
| Domain | Established finding | Evidence/model | Key quantitative or variant detail | Caveat |
|---|---|---|---|---|
| Phenotype and epidemiology | UV-sensitive syndrome (UVSS) is a mild, usually isolated cutaneous photosensitivity disorder characterized by exaggerated sunburn, freckling or pigmentary change, telangiectasia, and xerosis on sun-exposed skin; classic Cockayne neurologic, developmental, and systemic abnormalities are absent. | Aggregated case literature and reviews; DOI: 10.1016/j.mrfmmm.2014.11.003 and 10.47391/JPMA.03-476 (spivak2015photosensitivehumansyndromes. pages 4-6, muzammal2021themoleculargenetics pages 1-2, muzammal2021themoleculargenetics pages 3-5) | A 2021 review counted 18 patients from nine families of Japanese, French, Israeli, Iranian, and Pakistani ancestry. | Extreme rarity and likely underdiagnosis preclude reliable incidence, prevalence, penetrance, sex-ratio, or phenotype-frequency estimates. The reported 1:100,000 prevalence lacks population surveillance support. No tumor predisposition is established, but limited cohorts cannot prove zero risk. |
| ERCC6/CSB | Biallelic ERCC6 loss can cause UVSS1 rather than Cockayne syndrome, showing that genotype alone does not fully explain the clinical difference between these TC-NER disorders. | Human patients, fibroblast complementation, and molecular studies; DOI: 10.1073/pnas.0404587101 and 10.1038/ng.2229 (nakazawa2012mutationsinuvssa pages 19-22, nakazawa2012mutationsinuvssa pages 22-24) | Two reported patients were homozygous for ERCC6 c.229C>T (p.Arg77Ter), producing severe N-terminal truncation or absence of CSB. | Some secondary sources give inconsistent cDNA numbering for p.Arg77Ter; HGVS should be validated against the specified transcript. ERCC6 variants more commonly cause Cockayne syndrome. |
| ERCC8/CSA | Biallelic ERCC8 variants cause UVSS2; CSA is a substrate-receptor component of the CRL4CSA ubiquitin-ligase complex involved in TC-NER assembly. | Human cases, segregation, and patient-cell studies; DOI: 10.1038/ng.2229 and 10.2340/00015555-3032 (nakazawa2012mutationsinuvssa pages 22-24, li2019twonovelmutations pages 2-2) | Reported alleles include homozygous c.1083G>T (p.Trp361Cys) and c.582G>T plus c.769G>A (p.Gly257Arg) in a Chinese case; c.769G>A was reported below 0.01% in a Chinese dataset. | ERCC8 also causes Cockayne syndrome type A, so variant-specific functional and clinical context is essential. Current ClinVar classifications and gnomAD frequencies require independent verification. |
| UVSSA | Biallelic loss-of-function variants in UVSSA cause UVSS3 or UVSS-A and impair recovery of transcription after UV by disrupting TC-NER recruitment or stabilization. | Whole-exome sequencing, patient fibroblasts, complementation, and functional assays; DOI: 10.1038/ng.2229 (muzammal2021themoleculargenetics pages 2-3, nakazawa2012mutationsinuvssa pages 19-22) | Reported variants include c.367A>T (p.Lys123Ter), c.94T>C (p.Cys32Arg), c.87delG (p.Ile31PhefsTer9), and c.1040G>A, reported as a codon-347 truncating allele. | Secondary sources inconsistently label c.1040G>A as p.Trp347Ter or p.Tyr347Ter; transcript and reference-sequence validation is mandatory. Population frequencies and ACMG classifications were not uniformly reported. |
| Cellular diagnostics | UVSS cells show increased UV cytotoxicity and defective recovery of RNA synthesis after UV, while global-genome photoproduct repair or unscheduled DNA synthesis is relatively preserved, indicating selective TC-NER deficiency. | Cultured patient fibroblasts assessed by post-UV survival, recovery of RNA synthesis, unscheduled DNA synthesis, and complementation (spivak2015photosensitivehumansyndromes. pages 4-6, nakazawa2012mutationsinuvssa pages 19-22, li2019twonovelmutations pages 2-2) | Characteristic qualitative pattern: low UV survival plus abnormal recovery of RNA synthesis with near-normal global repair. | These are specialized assays without universal clinical cutoffs. Molecular confirmation of biallelic pathogenic variants is preferred. |
| Canonical TC-NER | A transcription-blocking UV photoproduct stalls RNA polymerase II; CSB binds first, recruits CRL4CSA or CSA, and facilitates ELOF1-dependent UVSSA positioning. UVSSA helps inactivate stalled polymerase and recruit TFIIH; XPA, RPA, XPG, and XPF-ERCC1 then support verification, dual incision, repair synthesis, and ligation. | Patient cells, isogenic knockout cells, biochemistry, and structural biology; DOI: 10.1038/ng.2229 and 10.1101/707216 (nakazawa2012mutationsinuvssa pages 19-22, muzammal2021themoleculargenetics pages 3-5, weegen2019thesequentialand pages 11-13) | UVSSA contains an N-terminal CSA-interacting region and a C-terminal TFIIH-interacting region around amino acids 400–500. | The pathway integrates multiple experimental systems. Some early models of RNAPII backtracking and degradation have been refined by later structural work. |
| 2024 structural advance | Cryo-EM and functional work showed that ELOF1 positions UVSSA and CRL4CSA on arrested Pol II, activating Pol II ubiquitylation. A TFIIS-like UVSSA element enters the Pol II pore and prevents TFIIS-mediated transcription reactivation, while other UVSSA regions promote TFIIH recruitment. | Structural, biochemical, immunoprecipitation, complementation, and nascent-RNA assays; February 2024; DOI: 10.1038/s41594-023-01207-0 (kokic2024structuralbasisfor pages 11-11, kokic2024structuralbasisfor pages 9-11) | UVSSA zinc-finger and K414-site mutants could preserve Pol II ubiquitylation while reducing TFIIH interaction, separating polymerase inactivation from repair recruitment. | Primarily mechanistic work in reconstituted complexes and cultured cells, not a clinical or natural-history study; direct genotype-phenotype prediction remains uncertain. |
| 2024 interstrand-crosslink finding | UVSSA also facilitates transcription-coupled repair of DNA interstrand crosslinks: loss sensitized human cells to crosslinking agents, delayed repair, and impaired a single-ICL reporter; rescue required intact UVSSA-TFIIH interaction. | Human HAP1 and MCF10A cells, clonogenic assays, reporter repair, chromatin fractionation, co-immunoprecipitation, and proteomics; DOI: 10.1101/2023.05.10.538304 (liebau2024transcriptioncoupledrepairof pages 7-8, liebau2024transcriptioncoupledrepairof pages 5-7, liebau2024transcriptioncoupledrepairof pages 1-3) | UVSSA loss reduced reporter ICL-repair efficiency by approximately 50%; F408A/V411A, defective in TFIIH binding, failed to rescue. | Initially reported as a preprint; relevance to untreated UVSS patients and clinical crosslinker toxicity is unproven. |
| Management and trials | Care is preventive and supportive: rigorous UV avoidance, broad-spectrum sunscreen, UV-protective clothing and gloves, sunglasses, environmental UV controls, dermatologic surveillance, emollients, genetic counseling, and cascade testing. | Expert-review recommendations and photoprotection practice; DOI: 10.47391/JPMA.03-476 (muzammal2021themoleculargenetics pages 1-2, muzammal2021themoleculargenetics pages 5-6) | No disease-modifying drug, gene therapy, validated pharmacogenomic strategy, response rate, or UVSS-specific interventional trial was identified. | Recommendations are extrapolated from pathophysiology and related photodermatoses rather than controlled UVSS trials. Topical corticosteroids should be used only for clinically indicated inflammation. |
Table: Compact evidence table summarizing the phenotype, causal genes and variants, diagnostic cellular signature, TC-NER mechanism, 2024 mechanistic advances, and present management of UV-sensitive syndrome. Major evidence limitations and nomenclature issues are identified explicitly.
UVSS is a hereditary photosensitivity syndrome in which defective repair of transcription-blocking DNA lesions produces an isolated or predominantly cutaneous phenotype. Common names include UV-sensitive syndrome, ultraviolet-sensitive syndrome, UVSS, and UV-sensitive syndrome A/UVSS-A for UVSSA-associated disease. Historical molecular subclasses are UVSS1 (ERCC6), UVSS2 (ERCC8), and UVSS3/UVSS-A (UVSSA). It is distinct from xeroderma pigmentosum (XP), CS, and photosensitive trichothiodystrophy (TTD). (spivak2015photosensitivehumansyndromes. pages 4-6, muzammal2021themoleculargenetics pages 1-2, nakazawa2012mutationsinuvssa pages 22-24)
This report is based on aggregated disease resources, published kindreds, individual case reports, patient-derived fibroblasts, and engineered cell systems—not longitudinal electronic-health-record data.
UVSS is caused by germline biallelic pathogenic variants affecting TC-NER:
Family history, parental consanguinity, and ancestry from a kindred carrying a pathogenic allele increase genetic risk, but UVSS is not restricted to one population. There is no evidence for polygenic susceptibility loci, modifier genes, anticipation, or a reproducible founder effect. Phenotypic divergence between UVSS and CS despite involvement of ERCC6 or ERCC8 indicates that allelic context and presently unresolved modifiers or repair-independent functions influence expressivity. This is a mechanistic inference, not an established modifier-gene model. (nakazawa2012mutationsinuvssa pages 22-24)
Solar or artificial ultraviolet radiation, especially wavelengths that generate cyclobutane pyrimidine dimers and 6-4 photoproducts, is the essential environmental trigger. Genotype creates deficient TC-NER; UV exposure creates transcription-blocking lesions; together they produce acute sunburn and chronic pigmentary change. UV exposure does not cause the inherited disorder, but strongly controls manifestation and severity. There is no established contribution from smoking, diet, alcohol, exercise, occupational chemicals, or infection. (spivak2015photosensitivehumansyndromes. pages 4-6, muzammal2021themoleculargenetics pages 3-5)
No protective allele has been established. Environmental protection consists of reducing UV dose through avoidance, clothing, sunscreens, UV-filtering eyewear, window films, and control of indoor UV sources. These measures reduce lesion formation rather than correcting the repair defect. (muzammal2021themoleculargenetics pages 1-2, muzammal2021themoleculargenetics pages 5-6)
Suggested ontology/chemical annotations: ultraviolet radiation; CHEBI:17627 for nitrate or unrelated entities is not appropriate—UV is a physical exposure, not a chemical. Specific UV-photoproduct CHEBI identifiers should be ontology-validated before ingestion.
| Phenotype | Type and course | Frequency/evidence | Suggested HPO term |
|---|---|---|---|
| Photosensitivity/exaggerated sunburn | Symptom/sign; usually recognized in childhood after sun exposure; recurrent and exposure-dependent | Core feature, but no defensible percentage | Photosensitivity (HP:0000992); exaggerated sunburn, ontology validation advised |
| Freckling or hyperpigmentation on exposed skin | Physical manifestation; chronic after repeated exposure | Common/core qualitative feature | Freckling (HP:0001480); abnormal skin pigmentation (HP:0001000) |
| Telangiectasia | Cutaneous sign; variable | Reported across cases | Telangiectasia (HP:0001009) |
| Xerosis/dry skin | Cutaneous sign; variable, generally mild | Repeatedly reported | Dry skin (HP:0000958) |
| Cellular UV hypersensitivity | Laboratory/cellular abnormality | Characteristic in tested patient fibroblasts | Cellular sensitivity to UV; exact HPO term should be validated |
| Defective recovery of RNA synthesis after UV | Functional laboratory abnormality | Characteristic TC-NER signature | No routinely used clinical HPO term; encode as assay result/GO annotation |
| Normal or near-normal global-genome repair | Negative laboratory discriminator | Characteristic relative to XP | Encode as diagnostic evidence, not a patient phenotype |
| Absence of progressive neurologic/developmental disease | Important negative finding | Distinguishes UVSS from CS | Do not encode absent phenotypes as positive associations |
The disease is generally mild and non-progressive systemically, while cutaneous injury is recurrent and cumulative with exposure. Available reports do not support intellectual disability, microcephaly, growth failure, sexual immaturity, premature aging, or internal-organ disease as typical UVSS manifestations. (spivak2015photosensitivehumansyndromes. pages 4-6, muzammal2021themoleculargenetics pages 2-3, muzammal2021themoleculargenetics pages 3-5)
No UVSS-specific EQ-5D, SF-36, PROMIS, disability, or work/school-participation study was identified. Likely burdens include activity restriction, heat and discomfort from protective clothing, anxiety about sunlight, cosmetic effects of pigmentary change, and recurrent painful burns; these are clinically plausible but have not been quantified in UVSS cohorts.
These are germline variants. The prevailing consequence is loss of function, destabilization, defective partner binding, or failure to recruit the repair machinery. A uniform ACMG/AMP reassessment and current ClinVar/gnomAD query were not available from the retrieved evidence; therefore, historical disease attribution should not automatically be converted into a present-day “pathogenic” ClinVar assertion. No somatic cause, recurrent chromosomal abnormality, repeat expansion, mitochondrial variant, or disease-specific epigenetic signature is established.
No validated modifier gene, protective allele, methylation signature, histone mark, or chromatin-level diagnostic biomarker has been demonstrated for UVSS. Ubiquitin and SUMO regulation are central post-translational mechanisms in TC-NER, but they are not inherited epigenetic causes. UVSSA interacts functionally with USP7, while CSA is part of CRL4CSA; these are pathway partners rather than established UVSS modifier genes. (kokic2024structuralbasisfor pages 11-11, weegen2019thesequentialand pages 11-13)
The major non-genetic determinant is cumulative UV exposure from sunlight, tanning devices, germicidal lamps, welding arcs, and other artificial sources. UV dose, wavelength, exposed surface area, and effectiveness of protection are expected to shape severity. No infectious agent or zoonotic process is involved. Evidence does not support diet, tobacco, alcohol, pollutants, or exercise as causal factors. Crosslinking chemicals and aldehydes are mechanistically relevant to the broader transcription-coupled-repair pathway, but their clinical importance in UVSS remains unproven. (liebau2024transcriptioncoupledrepairof pages 7-8, liebau2024transcriptioncoupledrepairof pages 1-3, liebau2024transcriptioncoupledrepairof pages 8-11)
Upstream events are lesion formation, Pol II arrest, CSB/CSA/ELOF1/UVSSA assembly, and ubiquitin regulation. Downstream events are TFIIH recruitment, helix opening, dual incision, repair synthesis, transcription recovery, and cell survival. Global-genome NER is comparatively preserved, explaining why UVSS is milder and apparently less cancer-prone than XP. Why UVSS lacks the neurodegeneration and progeria of CS remains incompletely resolved; authoritative interpretation favors additional transcriptional, mitochondrial, or repair-independent functions of CSA/CSB in CS rather than TC-NER deficiency alone. (spivak2015photosensitivehumansyndromes. pages 4-6, nakazawa2012mutationsinuvssa pages 22-24, li2019twonovelmutations pages 2-2)
Kokic and colleagues used cryo-EM, biochemical assays, immunoprecipitation, mutant complementation, and nascent-RNA measurements to show that ELOF1 acts as an adaptor positioning UVSSA and CRL4CSA, and that the UVSSA TFIIS-like element blocks reactivation of arrested Pol II. Their abstract states: “ELOF1 serves as an adaptor to stably position UVSSA and CRL4CSA on arrested Pol II” and that a UVSSA element “extends through the Pol II pore, thus preventing reactivation of Pol II by TFIIS.” Published February 2024, DOI: https://doi.org/10.1038/s41594-023-01207-0. (kokic2024structuralbasisfor pages 11-11, kokic2024structuralbasisfor pages 9-11)
A 2024 human-cell study extended UVSSA function beyond canonical UV-photoproduct repair to transcription-coupled interstrand-crosslink repair. UVSSA loss reduced single-ICL reporter repair by approximately 50%, and a TFIIH-binding-defective F408A/V411A UVSSA mutant failed to rescue. The preprint abstract states: “Inactivation of UVSSA sensitizes human cells to ICL-inducing drugs, and delays ICL repair.” Preprint posted in 2024, DOI: https://doi.org/10.1101/2023.05.10.538304. This finding is mechanistically important, but its relevance to untreated patients or drug toxicity is not established. (liebau2024transcriptioncoupledrepairof pages 7-8, liebau2024transcriptioncoupledrepairof pages 5-7, liebau2024transcriptioncoupledrepairof pages 1-3)
Recent work also distinguishes lesion-specific branches: CSA and CSB are required for transcription-coupled DNA–protein-crosslink repair, whereas downstream UVSSA and XPA are dispensable in at least one 2024 experimental system. Therefore, not every transcription-blocking lesion uses canonical UVSSA-dependent TC-NER.
No UVSS-specific transcriptomic, proteomic, metabolomic, lipidomic, single-cell, spatial-transcriptomic, or clinical multi-omics signature has been validated. Proteomics and structural methods have mapped repair-complex interactions, but not a patient diagnostic signature.
The primary organ is the skin, especially chronically sun-exposed face, neck, hands, and forearms. The relevant tissues are epidermis and superficial dermis; likely target populations include keratinocytes, melanocytes, and dermal fibroblasts. Ocular surfaces may receive UV exposure, but a consistent UVSS-specific ocular phenotype was not established. No characteristic nervous-system, endocrine, cardiovascular, respiratory, renal, gastrointestinal, musculoskeletal, or immune involvement is supported. Lesions are exposure-distributed rather than inherently unilateral; exposed sites are generally bilateral but may be asymmetric according to behavior and shielding. (spivak2015photosensitivehumansyndromes. pages 4-6, muzammal2021themoleculargenetics pages 3-5)
Suggested anatomy: skin of body (UBERON:0002097), epidermis (UBERON:0001003), dermis (UBERON:0002067); nucleus (GO:0005634) and chromatin are the principal subcellular compartments. Exact regional UBERON identifiers should be validated before ingestion.
UVSS is congenital at the molecular level but generally becomes clinically evident in infancy or childhood after meaningful UV exposure. Onset is exposure-provoked rather than spontaneous. Acute episodes consist of exaggerated sunburn; freckling, dryness, and telangiectasia accumulate chronically. There are no validated disease stages. The underlying repair defect is lifelong, while manifestations can be markedly reduced by photoprotection. Spontaneous molecular remission does not occur; apparent clinical remission reflects reduced exposure. Childhood is a critical prevention period because early cumulative UV injury can be avoided. Quantitative progression rates and longitudinal natural-history cohorts are unavailable. (spivak2015photosensitivehumansyndromes. pages 4-6, muzammal2021themoleculargenetics pages 1-2)
Inheritance is autosomal recessive. For two carrier parents, the conventional per-pregnancy risks are 25% affected, 50% carrier, and 25% unaffected/non-carrier. Penetrance appears high for cellular UV sensitivity and photosensitivity among biallelic cases, but formal age-dependent penetrance has not been measured. Cutaneous expressivity is variable and strongly exposure-dependent. There is no evidence of anticipation. Germline mosaicism has not been documented but cannot be excluded in a family with an apparently de novo allele. (muzammal2021themoleculargenetics pages 1-2, muzammal2021themoleculargenetics pages 3-5)
The 2021 literature synthesis reported 18 patients from nine families across Japan, France, Israel, Iran, and Pakistan. Consanguinity contributed to ascertainment in some families, but no reliable ethnicity-specific prevalence, geographic incidence, carrier frequency, sex ratio, or age distribution exists. The published 1:100,000 estimate should be treated as conjectural; a case count this small is incompatible with precise worldwide prevalence estimation. (muzammal2021themoleculargenetics pages 1-2)
Patient fibroblasts characteristically show reduced survival after 254-nm UV and deficient recovery of RNA synthesis (RRS), with relatively preserved unscheduled DNA synthesis (UDS) or global photoproduct repair. Complementation can assign a repair group. These assays are highly informative but specialized, non-standardized across routine laboratories, and lack universal clinical cutoffs. (spivak2015photosensitivehumansyndromes. pages 4-6, nakazawa2012mutationsinuvssa pages 19-22, li2019twonovelmutations pages 2-2)
A multigene panel is the efficient first test. Single-gene testing is appropriate only when a familial variant is known. WES identified UVSSA in the landmark study and is useful for panel-negative cases; WGS may detect deep-intronic, regulatory, or structural alleles but has no UVSS-specific validated yield. RNA sequencing can establish aberrant splicing in selected cases. CMA, karyotyping, FISH, mitochondrial testing, and repeat-expansion testing are not first-line unless independent clinical findings indicate them. Prenatal and preimplantation testing become technically feasible once familial pathogenic variants are established. (nakazawa2012mutationsinuvssa pages 19-22, nakazawa2012mutationsinuvssa pages 22-24)
There are no universally accepted UVSS clinical criteria and no population or newborn screening program. Cascade testing of relatives is appropriate after molecular confirmation.
Published patients generally have mild, skin-limited disease without the shortened survival, neurodegeneration, or multisystem morbidity typical of CS. No 5-year or 10-year survival, mortality rate, or life-expectancy estimate exists. No tumor had been reported in the 2015 synthesis, and subsequent reviews continue to describe absent cancer predisposition; nevertheless, sparse case numbers and follow-up mean that routine dermatologic surveillance remains prudent. (spivak2015photosensitivehumansyndromes. pages 4-6, muzammal2021themoleculargenetics pages 1-2, muzammal2021themoleculargenetics pages 3-5)
Morbidity is dominated by painful burns, cumulative pigmentary change, strict lifestyle constraints, and potential psychosocial burden. Prognosis should improve with early, sustained photoprotection. No validated prognostic biomarker exists; likely determinants are cumulative UV dose, adherence to protection, and residual TC-NER function, but these have not been modeled quantitatively.
There is no approved disease-modifying pharmacotherapy, gene therapy, RNA therapy, cell therapy, or surgical correction. Management is preventive and supportive:
No UVSS-specific treatment-response rates, adverse-event datasets, pharmacogenomic guidance, combination-treatment algorithm, or interventional ClinicalTrials.gov study was identified. Experimental UVSSA targeting in MYC-driven cancer and the association between UVSSA expression and crosslinker resistance are oncology applications, not treatments for UVSS. (liebau2024transcriptioncoupledrepairof pages 7-8, liebau2024transcriptioncoupledrepairof pages 8-11)
Suggested NCIT concepts: Sun Avoidance; Sunscreen; Protective Clothing; Genetic Counseling; Genetic Testing; Dermatologic Examination; Skin Biopsy. Exact NCIT codes should be validated against the current thesaurus.
Primary prevention of genotype is not possible after conception. Reproductive options include carrier testing, partner testing, prenatal diagnosis, and preimplantation genetic testing for a known familial genotype. Primary prevention of manifestations is immediate lifelong UV minimization. Secondary prevention consists of early diagnosis, cascade testing, surveillance of exposed skin, and prompt evaluation of new lesions. Tertiary prevention consists of preventing recurrent burns, treating xerosis/inflammation, and mitigating psychosocial and educational restrictions. Vaccination and antimicrobial prophylaxis have no disease-specific role. Public-health measures include accurate UV-risk education and accommodation at school or work. (muzammal2021themoleculargenetics pages 1-2, muzammal2021themoleculargenetics pages 5-6)
No naturally occurring veterinary disorder confidently equivalent to human UVSS was identified in the retrieved evidence. Orthologues of UVSSA, ERCC8, and ERCC6 are evolutionarily conserved across mammals and many eukaryotes, supporting comparative study of transcription-coupled repair. UVSS is noninfectious and has no transmission or zoonotic potential. NCBI Taxonomy identifiers relevant to laboratory work include Homo sapiens 9606 and Mus musculus 10090. Species-specific NCBI Gene and VBO breed identifiers require direct database verification.
The strongest disease-relevant systems are:
Mouse models of broader TCR and aldehyde-clearance defects demonstrate transcription-associated endogenous damage, but a validated mouse model reproducing the isolated mild human UVSS phenotype was not established by the retrieved evidence. No natural canine, livestock, zebrafish, Drosophila, or C. elegans UVSS counterpart was confirmed.
The causal-gene and cellular-repair assignments are strong because they combine human segregation, patient fibroblasts, complementation, and mechanistic experiments. Clinical frequency and prognosis evidence are weak because the literature contains very few patients, heterogeneous follow-up, and no registry. The frequently repeated “no cancer” statement means no established excess has been observed, not that excess risk has been statistically excluded. Likewise, the quoted prevalence of 1:100,000 is not a defensible epidemiologic statistic. Variant HGVS, current ClinVar classification, gnomAD frequency, HGNC IDs, and some ontology codes should be validated directly against current reference databases before production ingestion.
PMIDs explicitly recoverable from the disease-target evidence include 22466610, 22466611, and 22466612 for the 2012 UVSSA discovery series; 15486090 for the ERCC6/UVSS report; 19329487 and 25655951 for ERCC8/TC-NER-related evidence. These identifiers should be reconciled to titles in PubMed before automated import. (OpenTargets Search: UV-sensitive syndrome)
References
(spivak2015photosensitivehumansyndromes. pages 4-6): Graciela Spivak and Philip C. Hanawalt. Photosensitive human syndromes. Mutation research, 776:24-30, Jun 2015. URL: https://doi.org/10.1016/j.mrfmmm.2014.11.003, doi:10.1016/j.mrfmmm.2014.11.003. This article has 34 citations and is from a peer-reviewed journal.
(muzammal2021themoleculargenetics pages 1-2): Muhammad Muzammal, Muhammad Zeeshan Ali, Safeer Ahmad, Shawana Huma, Rizwan, Sohail Ahmad, Ansar Ahmad Abbasi, Saadullah Khan, and Muzammil Ahmad Khan. The molecular genetics of uv-sensitive syndrome; a rare dermal anomaly. Jul 2021. URL: https://doi.org/10.47391/jpma.03-476, doi:10.47391/jpma.03-476. This article has 14 citations.
(li2019twonovelmutations pages 2-2): Yue Li, Luyao Zheng, Fuying Chen, Z. Yao, and Ming Li. Two novel mutations in the ercc8 gene in a patient with ultraviolet-sensitive syndrome. Acta dermato-venereologica, 99 1:117-118, Jan 2019. URL: https://doi.org/10.2340/00015555-3032, doi:10.2340/00015555-3032. This article has 3 citations and is from a domain leading peer-reviewed journal.
(muzammal2021themoleculargenetics pages 3-5): Muhammad Muzammal, Muhammad Zeeshan Ali, Safeer Ahmad, Shawana Huma, Rizwan, Sohail Ahmad, Ansar Ahmad Abbasi, Saadullah Khan, and Muzammil Ahmad Khan. The molecular genetics of uv-sensitive syndrome; a rare dermal anomaly. Jul 2021. URL: https://doi.org/10.47391/jpma.03-476, doi:10.47391/jpma.03-476. This article has 14 citations.
(nakazawa2012mutationsinuvssa pages 19-22): Yuka Nakazawa, Kensaku Sasaki, Norisato Mitsutake, Michiko Matsuse, Mayuko Shimada, Tiziana Nardo, Yoshito Takahashi, Kaname Ohyama, Kosei Ito, Hiroyuki Mishima, Masayo Nomura, Akira Kinoshita, Shinji Ono, Katsuya Takenaka, Ritsuko Masuyama, Takashi Kudo, Hanoch Slor, Atsushi Utani, Satoshi Tateishi, Shunichi Yamashita, Miria Stefanini, Alan R Lehmann, Koh-ichiro Yoshiura, and Tomoo Ogi. Mutations in uvssa cause uv-sensitive syndrome and impair rna polymerase iio processing in transcription-coupled nucleotide-excision repair. Nature Genetics, 44:586-592, Apr 2012. URL: https://doi.org/10.1038/ng.2229, doi:10.1038/ng.2229. This article has 246 citations and is from a highest quality peer-reviewed journal.
(nakazawa2012mutationsinuvssa pages 22-24): Yuka Nakazawa, Kensaku Sasaki, Norisato Mitsutake, Michiko Matsuse, Mayuko Shimada, Tiziana Nardo, Yoshito Takahashi, Kaname Ohyama, Kosei Ito, Hiroyuki Mishima, Masayo Nomura, Akira Kinoshita, Shinji Ono, Katsuya Takenaka, Ritsuko Masuyama, Takashi Kudo, Hanoch Slor, Atsushi Utani, Satoshi Tateishi, Shunichi Yamashita, Miria Stefanini, Alan R Lehmann, Koh-ichiro Yoshiura, and Tomoo Ogi. Mutations in uvssa cause uv-sensitive syndrome and impair rna polymerase iio processing in transcription-coupled nucleotide-excision repair. Nature Genetics, 44:586-592, Apr 2012. URL: https://doi.org/10.1038/ng.2229, doi:10.1038/ng.2229. This article has 246 citations and is from a highest quality peer-reviewed journal.
(muzammal2021themoleculargenetics pages 2-3): Muhammad Muzammal, Muhammad Zeeshan Ali, Safeer Ahmad, Shawana Huma, Rizwan, Sohail Ahmad, Ansar Ahmad Abbasi, Saadullah Khan, and Muzammil Ahmad Khan. The molecular genetics of uv-sensitive syndrome; a rare dermal anomaly. Jul 2021. URL: https://doi.org/10.47391/jpma.03-476, doi:10.47391/jpma.03-476. This article has 14 citations.
(weegen2019thesequentialand pages 11-13): Yana van der Weegen, Hadar Golan Berman, Tycho E.T. Mevissen, Katja Apelt, Román González-Prieto, Elisheva Heilbrun, Alfred C.O. Vertegaal, Diana van den Heuvel, Johannes C. Walter, Sheera Adar, and Martijn S. Luijsterburg. The sequential and cooperative action of csb, csa and uvssa targets the tfiih complex to dna damage-stalled rna polymerase ii. bioRxiv, Jul 2019. URL: https://doi.org/10.1101/707216, doi:10.1101/707216. This article has 5 citations.
(kokic2024structuralbasisfor pages 11-11): Goran Kokic, George Yakoub, Diana van den Heuvel, Annelotte P. Wondergem, Paula J. van der Meer, Yana van der Weegen, Aleksandar Chernev, Isaac Fianu, Thornton J. Fokkens, Sonja Lorenz, Henning Urlaub, Patrick Cramer, and Martijn S. Luijsterburg. Structural basis for rna polymerase ii ubiquitylation and inactivation in transcription-coupled repair. Nature Structural & Molecular Biology, 31:536-547, Feb 2024. URL: https://doi.org/10.1038/s41594-023-01207-0, doi:10.1038/s41594-023-01207-0. This article has 64 citations and is from a highest quality peer-reviewed journal.
(kokic2024structuralbasisfor pages 9-11): Goran Kokic, George Yakoub, Diana van den Heuvel, Annelotte P. Wondergem, Paula J. van der Meer, Yana van der Weegen, Aleksandar Chernev, Isaac Fianu, Thornton J. Fokkens, Sonja Lorenz, Henning Urlaub, Patrick Cramer, and Martijn S. Luijsterburg. Structural basis for rna polymerase ii ubiquitylation and inactivation in transcription-coupled repair. Nature Structural & Molecular Biology, 31:536-547, Feb 2024. URL: https://doi.org/10.1038/s41594-023-01207-0, doi:10.1038/s41594-023-01207-0. This article has 64 citations and is from a highest quality peer-reviewed journal.
(liebau2024transcriptioncoupledrepairof pages 7-8): Rowyn C Liebau, Crystal Waters, Arooba Ahmed, Rajesh K Soni, and Jean Gautier. Transcription-coupled repair of dna interstrand crosslinks by uvssa. bioRxiv, May 2024. URL: https://doi.org/10.1101/2023.05.10.538304, doi:10.1101/2023.05.10.538304. This article has 4 citations.
(liebau2024transcriptioncoupledrepairof pages 5-7): Rowyn C Liebau, Crystal Waters, Arooba Ahmed, Rajesh K Soni, and Jean Gautier. Transcription-coupled repair of dna interstrand crosslinks by uvssa. bioRxiv, May 2024. URL: https://doi.org/10.1101/2023.05.10.538304, doi:10.1101/2023.05.10.538304. This article has 4 citations.
(liebau2024transcriptioncoupledrepairof pages 1-3): Rowyn C Liebau, Crystal Waters, Arooba Ahmed, Rajesh K Soni, and Jean Gautier. Transcription-coupled repair of dna interstrand crosslinks by uvssa. bioRxiv, May 2024. URL: https://doi.org/10.1101/2023.05.10.538304, doi:10.1101/2023.05.10.538304. This article has 4 citations.
(muzammal2021themoleculargenetics pages 5-6): Muhammad Muzammal, Muhammad Zeeshan Ali, Safeer Ahmad, Shawana Huma, Rizwan, Sohail Ahmad, Ansar Ahmad Abbasi, Saadullah Khan, and Muzammil Ahmad Khan. The molecular genetics of uv-sensitive syndrome; a rare dermal anomaly. Jul 2021. URL: https://doi.org/10.47391/jpma.03-476, doi:10.47391/jpma.03-476. This article has 14 citations.
(OpenTargets Search: UV-sensitive syndrome): Open Targets Query (UV-sensitive syndrome, 3 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.
(liebau2024transcriptioncoupledrepairof pages 8-11): Rowyn C Liebau, Crystal Waters, Arooba Ahmed, Rajesh K Soni, and Jean Gautier. Transcription-coupled repair of dna interstrand crosslinks by uvssa. bioRxiv, May 2024. URL: https://doi.org/10.1101/2023.05.10.538304, doi:10.1101/2023.05.10.538304. This article has 4 citations.
Checked with linkml-reference-validator 0.2.1.
| Outcome | Count |
|---|---|
| References checked | 9 |
| Resolved | 9 |
| Unresolved (possible confabulation) | 0 |
| Unverifiable | 0 |
| References weighed for topical relevance | 9 |
| On topic | 3 |
| Off topic | 0 |
All extracted references resolved successfully.
Checked with linkml-term-validator 0.4.5, through the ols: adapter.
| Outcome | Count |
|---|---|
| Terms checked | 16 |
| Resolved | 16 |
| Unresolved (possible confabulation) | 0 |
| Obsolete | 0 |
| Unverifiable | 0 |
| Terms whose name was checked | 1 |
| Terms named correctly | 0 |
| Terms named as a different term | 1 |
These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:
MONDO:0015797 (4 mentions) - the report calls it "if available"; MONDO calls it UV-sensitive syndrome