Shuhei Fukuro

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 patients 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 D XP 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. Hum Mutat 9:322–331, 1997.

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.

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.

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.