Nathan Milliner

Ultraviolet Sensitivity Syndrome, Option A

Ultraviolet Sensitivity Syndrome, UVSS, is a genetic disorder that is characterized by an

increased sensitivity to UV spectrum light due to the bodies inability to repair damage to DNA.

UVSS has an extremely low frequency, with only a handful of cases reported in literature, however

there is a high probability of the disorder going undiagnosed or being misdiagnosed as other similar

DNA repair deficiencies such as Cockanye syndrome. In this paper the symptoms, inheritance,

and morbidity will be examined as well as the specific DNA alterations of each variant of UVSS

and the accompanying protein deficiencies that define this disorder. Lastly methods for screening,

identification, and disease management will be examined.

Phenotypically individuals with UVSS do not express dramatic physical characteristic if

the even express any at all. Some of these physical traits include freckling, dryness, or

pigmentation after direct sun exposure. In some cases, subjects also exhibit telangiectasia, or small

clusters of enlarged blood vessels that are immediately subcutaneous, typically these clusters are

found on the cheeks and nose. In some cases, however subjects with UVSS do not exhibit any

visible physical expression. Unusually while UV damage has been linked to skin cancers, subjects

with UVSS do not exabit an increased risk of skin cancer when compared to the general population

(UV-Sensitive syndrome, 2018).

UVSS is an autosomal recessive disorder, thus both copies of the gene must have the

mutation. Heterozygotes do not typically show any symptoms of this disorder, and both parents

must have at least one copy of the gene for it to be passed on. Because UVSS is a polygenetic

disorder the subject must inherit the identically mutated genes from each parent for UVSS to
present. Additionally, because of its recessive nature it is very rare for an individual to pass on

UVSS to their offspring unless both parents have the syndrome.

Unfortunately, due to this disorders rarity and misattribution of symptoms it is difficult to

attach an average age to death as a result of UVSS, and with the limited pool of subjects affected

by UVSS in a given region it is impossible to predict for certainty what effect environment plays

in determining average life span. With UVSS as with other genetic repair disorder the cause of

death is the DNA becomes so damaged from UV radiation caused breaks that it ceases to function,

eventually leading to a build up of loss of function mutations in cells until the protein deficiency

becomes fatal. Because the genetic damage occurs at random there is no way to treat UVSS and

the effects are cumulative over the course of the life of the subject.

UVSS is broken down into three distinct disorders based on the specific gene that has

undergone mutation. These are simply named UVSS-1, UVSS-2, and UVSS-3. UVSS-1 is

characterized by impaired recovery of RNA synthesis, RSS, after being damaged by UV light as a

result of a defect in transcription-coupled nucleotide excision repair, TC-NER. UVSS-1 is

associated with the gene ERCC6. UVSS-2 likewise is characterized by impaired recovery of RNA

synthesis because of a defect in TC-NER, however it can also present with more sever phenotypical

expressions including neurological symptoms and skeletal abnormalities in a condition known as

Cockayne Syndrome type A. UVSS-2 is associated with the gene ERCC8. Lastly UVSS-3 like the

other two disorders is characterized by the impaired recovery of RNA synthesis during active

transcription from a defect in TC-NER. UVSS-3 is associated with the gene UVSSA (UV-

Sensitive Syndrome, 2018).

ERCC6, ERCC excision repair 6 chromatin remodeling factor, makes a protein known as

Cockayne syndrome B, CSB, which is involved in DNA repair during active replication, and also
seems to be involved in assisting with gene transcription. Researchers believe that when CSB is

normally functioning it helps remove RNA polymerase after it gets stuck at damaged DNA sites

so that repair occurs, and may also assist in restarting transcription after the repair is completed.

There are at least 60 known mutations of ERCC6 which results in Cockayne syndrome however

there is only one mutation that causes UVSS. In UVSS-1 ERCC6 undergoes a nonsense point

mutation known as Arg77Ter or R77X in which the arginine at position 77 is replaced by a stop

codon. This results in an abnormally short protein that breaks down almost immediately. It is

currently unclear as to how the loss of CSB causes UVSS-1 nor is it clear why the Arg77Ter

mutation does not present with the other symptoms of Cockayne syndrome. ERCC6 is located on

the long (q) arm of chromosome 10 at position 11.23 and is approximately 85,000 base pairs long

(ERCC6 gene, 2018).

ERCC8, ERCC excision repair 8 CSA ubiquitin ligase complex subunit, produces a protein

known as Cockayne syndrome A, CSA. In normal function this protein is involved in one of the

mechanisms for correcting DNA within genes that are undergoing transcription, however its

specific role is currently unclear. It is likely it interacts with other proteins to identify damaged

areas. Like ERCC6 there are more then 30 ERCC8 mutations that can cause Cockanye syndrome

while there is only one known mutation that results in UVSS. In UVSS-2 ERCC8 undergoes a

missense mutation known as Trp361Cys or W361C in which the amino acid tryptophan at position

361 is replaced by a cysteine. It is currently unknown how this mutation affects the function of the

protein nor how the abnormal CSA protein causes UVSS. Like with UVSS-1 it is unclear why this

mutation does not present with the other symptoms of Cockanye syndrome. ERCC8 is located on

the long (q) arm of chromosome 5 at position 12.1 and is just over 71,000 base pairs long (ERCC8,

2018).
 Lastly UVSSA, UV stimulated scaffold protein A, produces a protein that is involved in

repairing UV damage to DNA. When functioning normally the UVSSA protein helps remove RNA

polymerase from damaged DNA sites and unsure that CSB is not broken down by UV exposure.

There are three known mutations of UVSSA that cause UVSS-3, two missense mutations,

Lys123Ter and Cys32Arg, and a deletion of codon 87. Without a functioning UVSSA protein

DNA damaged from UV radiation cannot be repaired, however it is still unclear exactly how the

loss of function results in the phenotypic symptoms of UVSS-3. There are no other known

disorders associated with mutation of the UVSSA gene. UVSSA is located on the short (p) arm of

chromosome 4 at position 16.3 and is just over 46,000 base proteins (UVSSA Gene, 2018).

As can be seen there is are close genetic similarities between UVSS and Cockanye

syndrome which has contributed to the misdiagnosis of UVSS. UVSS is present from conception

and has not been known to develop spontaneously after birth and because of its rarity none of the

variations of UVSS are screened for specifically, however UVSS-1 and UVSS-2 can be identified

by some general screenings such as the DonerReady Customized Carrier Screen and the

FamilyReady Carrier Screen. Confirmation of the disease is done via genetic testing and can

consist of targeted variant analysis or region coding analysis. In total there are 11 tests for UVSS-

1 and UVSS-2. UVSS-3 is not identified by any general screenings and must be tested for

specifically. There are three tests for confirming UVSS-3 and can either be a deletion analysis or

a sequence analysis of the entire coding region. Currently UVSS-1 and UVSS-2 can only be tested

in the United States, Germany, Slovakia, and Austria while UVSS-3 can only be tested for in the

Untied States, Germany, and Portugal (Genetic Testing Registry, n.d.).

After confirmation of UVSS there are steps that can be taken to controlling the

disease, although presently there are no means of treating the disease itself or cures for any of the
versions of UVSS. Without a means to repair DNA the effects of UV damage is cumulative and

irreversible therefor the key to prevention is early identification so that exposure mitigation can be

started as soon as possible. Environmental conditions have the greatest impact on the speed of

advancement and onset of death.

When it comes to treating UVSS it is all about prevention and avoiding UV radiation.

Subjects with UVSS must avoid UV exposure as much as possible, by staying out direct sunlight

and avoiding secondary sources of UV radiation such as UV lamps and some types of florescent

lighting. Additionally, it is recommend that sunscreen always be used when outdoors during

daylight hours. According to the World Health Organization other outdoor precautions include

watching the UV index, being aware that not all shade produces complete barriers to sunlight, and

wearing protective clothing such as sunglasses with UV-A and UV-B protection, wide brimmed

hats, and tightly woven loose-fitting clothing (Cancer Council of Victoria, Australia, n.d.).

Children who are afflicted are at greater risk of exposure due to the dynamic state of growth that

they are in.

The other symptoms of UVSS can be controlled somewhat through proper skin care and

moisturizing to treat the dry skin and prevent infection. In the cases where telangiectasia forms,

the blood vessels can be treated by laser therapy although this is a very costly and painful procedure

that must be repeated frequently and only cosmetic in nature except in extremely severe cases.

Freckling can also be treated with laser therapy, though there are no known medical reasons for

the removal of freckles. The skin pigmentation that occurs from direct sun exposure is usually

temporary, and any sunburns should be treated normally as they would be for the general

population.
 In conclusion, while being a very rare disease, UVSS is a tragic disorder with no treatment

and no chance of recovery. As can be seen much research is still needed in regard to the specific

functionality of the genes responsible for UVSS, until then the only thing those who have UVSS

can do is prevent as much damage as possible while trying to live normal lives.

References
Cancer Council of Victoria, Australia. (n.d.). Sun Prorection. Retrieved Apr 25, 2018, from World Health
Organization: www.who.int/uv/sun_protection/en/
ERCC6 gene. (2018, Apr 17). Retrieved Apr 25, 2018, from Genetics Home Reference:
https://ghr.nlm.nih.gov/gene/ERCC6
ERCC8. (2018, Apr 17). Retrieved Apr 25, 2018, from Genetic Home Reference:
https://ghr.nlm.nih.gov/gene/ERCC8
Genetic Testing Registry. (n.d.). Retrieved Apr 25, 2018, from National Center for Biotechnology
Information: https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=C3553328&filter=testtype:clinical
UV-Sensitive syndrome. (2018, Apr 17). Retrieved Apr 25, 2018, from Genetics Home Reference:
https://ghr.nlm.nih.gov/condition/uv-sensitive-syndrome#
UV-Sensitive Syndrome. (2018, Apr 23). Retrieved Apr 25, 2018, from MalaCards:
www.malacards.org/card/uv_sensitive_syndrome
UVSSA Gene. (2018, Apr 17). Retrieved Apr 24, 2018, from Genetics Home Reference:
https://ghr.nlm.nih.gov/gene/UVSSA