Mutations in the XPD gene leading to xeroderma pigmentosum symptoms.

XP is a sun-sensitive and cancer-prone genetic disorder, consisting of eight (group A-G) genetically distinct complementation groups. Some XP group D patients exhibit clinical symptoms of other genetic disorders, CS, and TTD. The XP group D gene (XPD gene) product is required for nucleotide excision repair and is one of the components of basal transcription factor TFIIH as well. Therefore, different mutations in the XPD gene may result in a variety of clinical manifestations. Here we report on two causative mutations of the XPD gene in XP61OS, a Japanese XP group D patient who has only mild skin symptoms of XP without CS, TTD, or other neurological complications. One of the mutations was the 4-bp deletion at nucleotides 668-671, resulting in frameshift and truncation of the protein. The other was a nucleotide substitution leading to Ser-541 to Arg (S541R) in helicase domain IV of the XPD protein. The patient's father was heterozygous for the 4-bp deletion, while the mother was heterozygous for the S541R mutation. Thus, the parents were obligate carriers of the XP-D trait. The expression study showed that the XPD cDNA containing the deletion or the S541R missense mutation failed to restore the UV sensitivity of XP6BE, group DaXP cells, while the wild-type XPD cDNA restored it to the normal level. However, the transfectant expressing the XPD cDNA with the missense mutation was slightly more resistant than the parental XP6BE cells. These findings are consistent with the mild symptoms of the XP61OS patient.

Motor disturbance during REM sleep in group A xeroderma pigmentosum.

We investigated motor phenomena during rapid eye movement (REM) sleep in 13 patients with group A xeroderma pigmentosum aged from 11 to 39 months, and compared them with those obtained from 12 age-matched controls. At the time of sleep study, they had no abnormality on routine electrophysiological examinations. The amount of REM sleep and the incidence of motor phenomena during REM sleep in patients were similar to those in age-matched controls. However using the newly designated indices, we demonstrated disturbance on both the tonic motor inhibition occurring during the whole REM sleep period and the phasic one acting simultaneously with horizontal rapid eye movements in these patients. Since the motor inhibition during REM sleep is mediated by the subcortical structures, our study indicate that these structures are functionally impaired in group A xeroderma pigmentosum even during the early stage of the illness.

Chronic actinic dermatitis: a clinical and photobiological study in 6 Japanese patients.

Chronic actinic dermatitis (CAD) has distinct clinical features different from polymorphous light eruption (PLE). In order to clarify the difference between CAD and PLE, not only in clinical histories and findings but also in photobiological and histopathological reactions to phototests, we investigated 6 Japanese patients with CAD and performed provocative phototests which are our standardized methods in diagnosing PLE. On provocative phototests in CAD, pruritic papules were reproduced with smaller doses of UVB, at longer hours after irradiation (48-72 h) and they lasted for more days than in patients with PLE. Our study demonstrated that although milder cases of CAD and severe cases of PLE could not be distinguished clearly based on photobiological reactions alone, typical cases of CAD showed completely different provocative phototest results from those of PLE.

Xeroderma pigmentosum: recent clinical and photobiological aspects.

In Japan, more than 400 patients with xeroderma pigmentosum (XP) have been registered. The major groups are XP-A and variant, while clinically mild types of XP with intermediate levels of unscheduled DNA synthesis (UDS) have recently been increasing. The classical type of XP-A and some of the XP-D patients exhibit neurologic abnormalities. XP individuals display a marked increase in the frequency of skin malignancy. Development of skin malignancies appears to be related to the level of DNA repair capacity; the lower the capacity, the earlier and more frequently the skin tumors develop. Furthermore, the incidence of internal malignancy in XP patients is at least ten times higher than that for the Japanese general population over the age of 40 years. Cultured fibroblasts from XP patients exhibit higher sensitivity not only to UVC but also to UVB. The cellular sensitivity to UVB may correlate to photosensitivity in vivo from a study on a group E patient who showed age-related changes in photosensitivity and cellular sensitivity to UVB. We have also reviewed current status of molecular genetics in XP.

Photosensitivity in atopic dermatitis: demonstration of abnormal response to UVB.

It is a well-known fact among clinicians that sunlight may exacerbate atopic dermatitis (AD), but little is known beyond that. In a preliminary study investigating this phenomenon, 19 patients with AD were selected for phototests. All of them had a normal minimal erythema dose (MED). However, 3 patients (15.7%) demonstrated abnormal cutaneous responses 24-72 h after provocation with ultraviolet light B (UVB). None of the patients had a positive response to pure ultraviolet light A (UVA) irradiation of up to 9 J/cm2. The photobiological results of this study confirm the existence of photosensitivity in AD and indicate that UVB wavelengths are responsible for it.

Age-related changes in photosensitivity and cellular sensitivity to ultraviolet B in a xeroderma pigmentosum group E patient.

Skin phototesting and cellular sensitivity studies were performed in a patient with xeroderma pigmentosum (XP) complementation group E (XP80TO) at the ages of 50 and 55 years. She showed a reduced minimal erythema dose at both ages, but the dose at age 55 was much lower than that at age 50 when tested with monochromatic ultraviolet (UV) light (280, 290 and 300 nm). The cellular sensitivity to UVC (254 nm), UVB and UVA and UVC-induced unscheduled DNA synthesis were examined using fibroblasts obtained by skin biopsy at the ages of 50 and 55 (XP80TO-1 and XP80TO-2, respectively). DNA synthesis was similar in both cell lines. XP80TO-2 cells were more sensitive to UVB cytotoxicity than XP80TO-1 cells in both the dividing and quiescent phases, but both cell lines exhibited a similar sensitivity to UVC and UVA. These results suggest that the in vitro cellular sensitivity to UVB may correlate with the clinically observed erythema reaction. Further, the results suggest that some XP complementation group E cases at least may show an increase in photosensitivity in vivo and in vitro with aging.

Protective effect of dl-alpha-tocopherol on the cytotoxicity of ultraviolet B against human skin fibroblasts in vitro.

The effect of dl-alpha-tocopherol on ultraviolet light, 280-320 nm (UVB)-induced damage of human skin fibroblasts was studied by measuring the colony-forming ability, unscheduled DNA synthesis (UDS) and malondialdehyde (MDA) production. Regarding the cell toxicity, the values of the mean lethal dose (D0) of UV in fibroblast strains from 5 normal subjects were examined. D0 increased dose-dependently when the cells were cultured in the presence of dl-alpha-tocopherol at the concentration of 10-1000 micrograms/ml. UDS induced by 500 J/m2 UVB irradiation was not altered by treatment of 100 micrograms/ml dl-alpha-tocopherol. MDA did not increase after 500 J/m2 UVB irradiation in the fibroblasts cultured with 100 micrograms/ml dl-alpha-tocopherol, while MDA in the fibroblasts cultured without dl-alpha-tocopherol increased after irradiation. These results suggest that dl-alpha-tocopherol protects human skin fibroblasts against the cytotoxic effect of UVB, and its mechanism seems to be related to inhibition of UV-induced lipid peroxidation or to the antioxidation effect of dl-alpha-tocopherol.

Xeroderma pigmentosum group D patient bearing lentigo maligna without neurological symptoms.

A 35-year-old Japanese female patient with xeroderma pigmentosum (XP), registered as XP114TO, was assigned to complementation group D by the cell fusion complementation test. The patient had manifested moderate solar sensitivity and freckles by the age of 6 years. The skin phototest using 290- and 300-nm monochromatic ultraviolet (UV) light revealed slightly lowered minimal erythema doses at 24 h after irradiation. The XP114TO skin fibroblasts exhibited about the 6-fold higher sensitivity to the lethal effect of 254-nm UV as did normal cells. Unscheduled DNA synthesis (UDS) induced in XP114TO cells by 254-nm UV (10 J/m2) was 33% of normal, falling into the group D range of 25-50% UDS. The patient developed lentigo maligna on the right side of the nose. Unlike the typical XP group D cases in the West, she showed no neurological abnormalities.

Assignment of three patients with xeroderma pigmentosum to complementation group E and their characteristics.

Three cases belonging to xeroderma pigmentosum (XP) complementation group E were analyzed clinically and photobiologically. The three Japanese patients were a 50-yr-old female (XP80TO), a 42-yr-old female (XP81TO), and a 41-yr-old female (XP82TO). They were assigned to complementation group E by the cell hybridization study. All showed lowered minimal erythema doses between those of normal Japanese and XP group A subjects at wavelengths of 280, 290, and 300 nm of monochromatic ultraviolet (UV) light. Patients XP80TO and XP81TO, but not patient XP82TO, showed a delayed peak reaction at 48 h to UV erythema. All fibroblast strains from these patients had a reduced level of 40%-44% unscheduled DNA synthesis (UDS) after irradiation with 10 J/m2 of 254 nm UV. Primary cultured epidermal cells from these patients exhibited a relatively low level of UDS (ie, 38%-51% of normal epidermal cells). All of the group E fibroblast strains were twice as sensitive to 254 nm UV killing [n (extrapolation number) = 1.3-1.8, Do (mean lethal dose) = 2.2-2.8 J/m2)] as normal fibroblasts (n = 1.5, Do = 5.0 J/m2). All of the above group E patients had mild XP symptoms, but not neurological abnormalities, at the fifth decade of age. Patients XP80TO and XP81TO had developed skin malignancies (patients XP80TO developed three basaliomas; patient XP81TO developed two basaliomas) at the ages of 46 and 41 yr, respectively.