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Four types of possible founder mutations are responsible for 87% of Japanese patients with Xeroderma pigmentosum variant type
144
Letters to the Editor
LETTER TO THE EDITOR Four types of possible founder mutations are responsible for 87% of Japanese patients with Xeroderma pigmentosum variant type KEYWORDS Xeroderma pigmentosum variant type; Hot spots; Immunoprecipitation; Minimum erythema dose
Xeroderma pigmentosum (XP) is classified into nucleotide excision repair (NER) deficient types, A through G, as well as a variant type. XP-variant (XPV, OMIN: 278750) is characterized by late onset of clinical skin symptoms such as skin cancers. XP-V cells show proficient NER but display an exaggerated delay in the recovery of the replicative DNA synthesis after UV irradiation. XP occurs at higher frequency in Japan (1:22,000) [1] than in the United States (1:250,000) [2]. Approximately 50% of all Japanese patients with XP are assigned to XP-A and 25% to XP-V [2]. The responsible gene for XP-V was cloned and its
product was identified as DNA polymerase eta (POLH, Genebank accession number NM006502), which enables cells to synthesize the correct daughter strands, despite the presence of thymidine dimers, onto the UV-damaged template DNA [3,4]. After the cloning of POLH, genetic analysis revealed many mutation sites in the POLH gene in patients with XP-V [5—7]. We previously reported that an immunoprecipitation (IP) analysis with antiPOLH antibodies is a useful method for screening patients suspected of XP-V, showing clear coincidence between the molecular defect in the POLH gene and its protein loss [7], although this method has limitation that miss mis-sense mutation which generate a stable but non-functional protein. In this study after obtaining written informed consent, additional 13 Japanese patients were diagnosed as XP-V by IP analysis and POLH mutations were identified for those patients without 83 kDa POLH protein band. We combined 13 XP-V patients in this study together with 14 XP-V patients in our previous study [7] and analyzed both mutation frequency among Japanese patients (Fig. 1) and genotype—
Fig. 1 Mutation sites and its frequency of POLH gene in Japanese XP-V patients. (a) The mutation sites and the number of patients are indicated. ‘‘Homo’’ stands for homozygous mutation and ‘‘Hetero’’ stands for heterozygous mutation. As for the possible founder mutations, the allele frequencies were indicated. (b) Genotype and its predicted POLH protein. NLS stands for nuclear localization signal.
Cell strain
Age
Genotype
Amino acid changes
IP band
UDS (%)
Age onset of skin cancers BCC
SCC
MM
45
52 45
Homozygous/Hemizygous nonsense mutation XPV6HM d 53 C725G S 242 stop XPV4KO d 55 C725G S 242 stop XPV11HM d 69 G916T E 306 stop XPV10KO 62 G916T E 306 stop XPV6KO d 55 G916T E 306 stop XPV3 TK 69 G916T E 306 stop
Absent Absent Absent Absent Absent Absent
75 72 70 ND 92 89
37 45 59 41
Homozygous nonsense mutation XPV8KO 50 G916T XPV2HM d 68 C1066T
Absent Absent
ND 87
44 57
48
47.2
53.7
E 306 stop R 356 stop
C725G, G916T, C1066T average Homozygous/Hemizygous deletion XPV12HM d 43 del1661A XPV9KO
13
del1661A
XPV14KO e
71
del1661A
XPV17KO e
61
del1661A
Homozygous deletion XPV11KO 79 del1661A XPV13KO
67
del1661A
Absent
66
Absent
92
Absent
90—100
Absent
89.35
554 frameshift stop at 584 554 frameshift stop at 584
Absent
57.2
76
Absent
83
36
del1661A average Homozygous/ Hemizygous splicing mutation 54 G490T Frameshift or XPV7HM d large deletion# XPV10HM d 67 G490T Frameshift or large deletion# XPV12KO 49 G490T Frameshift or large deletion#
a
MED (mJ/cm2)
51
100 150 WNR
44 Multiple
150
—
136
Freckles
7—8 6—7
c
— — ND — — — + +
48
No Skin Cancers 71 No Skin Cancers
77 67 57.0
Consanguinity b
10
43
56
Sunburn
ND — ND — — ND
54 68
554 frameshift stop at 584 554 frameshift stop at 584 554 frameshift stop at 584 554 frameshift stop at 584
Photosensitivity
Letters to the Editor
Table 1 Genotype and phenotype in Japanese patients with XP-V
ND
ND
100
—
—
100
+
—
100
—
—
60
—
>116
—
14
+ +
67
Absent
115
47
—
6
ND
Absent
105
47
ND
13
ND
Absent
65
48
—
4
—
80
145
146
Table 1 (Continued )
Cell strain
Age
Genotype
Amino acid changes
IP band
UDS (%)
Age onset of skin cancers BCC
XPV15KO
28
G490T
XPV1TK
75
G490T
Homozygous splicing mutation 82 G490T XPV1HM d XPV2KO d
69
G490T
XPV5KO d
57
G490T
XPV2 TK
28
G490T/C1066T
MED (mJ/cm2)
Sunburn
Consanguinity b
Freckles
110
27
80
—
Absent
89
73
WNR
ND
Frameshift or large deletion# Frameshift or large deletion# Frameshift or large deletion#
Absent
109
71
57
120
+
7
+
Absent
91
22
45
60
—
5
+
Absent
75
45
70
+
7
+
56
WNR
NS
35
WNR 100
ND — —
24
WNR
ND
A117P
Faint
88
S 242 stop + K589T S 242 stop + K589T Frameshift or large deletion# + E 306 stop Frameshift or large deletion# + R 356 stop
Absent Absent Absent
96 ND 108
Absent
ND
Multiple 35 24
7
c
Absent
48.25
Compound heterozygote XPV8HM d 39 C725G/A1766C XPV16KO 35 C725G/A1766C XPV1KO d 34 G490T/G916T
MM
a
Frameshift or large deletion# Frameshift or large deletion#
G490T average Homozygous missense mutation XPV3KO d 50 G349C
SCC
Photosensitivity
— —
48.2 + 15 13 13
— — — —
Letters to the Editor
BCC: Basal cell carcinoma, SCC: Squamous cell carcinoma, MM: Malignant melanoma, NS: not specified, WNR: within normal range in terms of the institution standard, IP: immunoprecipitation, ND: no data. a MED for normal Japanese are between 60 and 140 mJ/cm2. b Experience of severe sunburn in their childhood according to patient’s history. c Age onset freckles on the sun-exposed area were indicated d Mutations for these patients are reported in ref. [7]. e Siblings. # 164 frameshift stop at 192, deletion from G-134 to K-163.
Letters to the Editor phenotype relationship (Table 1). Previously, we have reported that G490T was a possible hot spot. Here, we identified del1661A is the second most frequent mutation. Eighteen (33%) out of 54 alleles (27 patients) were G490T, 12 (22%) were del1661A, 11 (20%) were G916T and 6 (11%) were C725G. These four types of mutations were responsible for 47 (87%) out of 54 mutated alleles of Japanese patients with XP-V (Fig. 1a). Among Japanese XP-A patients, founder mutation has been indicated, where one particular type of mutation was detected in high frequency (85%) [1,8]. In XP-V also we identified four types of possible founder mutations, namely G490T, del1661A, G916T and C725G. Among 27 patients, 8 patients had consanguinity. Since XPV3KO is the only patient with homozygous G349C and his parents are second cousin, G349 C might be infrequent. Because most patients did not have consanguinity and all patients except XP14KO and XP17KO are not related and their origin were diverse, it could be possible that these mutations are not founder mutations but hot spots. However considering that all these mutations were not reported in countries other than Japan so far (Fig. 1a), it is likely that these mutations arose in Japan long time ago and spread over here. Two unrelated patients, XPV16KO in this study and XPV8HM [7] in the previous study, showed the same type of compound heterozygotes, C725G and A1766C. Although we have already confirmed a missense mutation A1766C is not a single nucleotide polymorphism [7], the second case of this type of compound heterozygote reconfirmed that A1766C should be the cause of the disease. The POLH protein consists of 713 amino acids and its polymerase activity resides entirely in the first 511 sequence [9], containing highly conserved among damage bypass replication proteins (Fig. 1b). We assessed genotype—phenotype relationships, by comparing clinical features including minimal erythema dose (MED), sun-induced freckles, age onset of skin cancers and repair ability in relation to the predicted amino acids (Fig. 1). Clinical features were summarized and arranged according to the genotype (Table 1). Unscheduled DNA synthesis levels were not significantly different among different genotypes. All patients except for XPV9KO and XPV17KO developed skin cancers. Among homozygous/hemizygous mutations detected, del1661A mutations cause frameshift at codon 554, which results in termination at codon 584 outside the catalytic domain, whereas C725G, G916T and C1066T cause a termination codon inside the catalytic domain. Thus, we compared clinical features of 6 patients having homozygous/hemizygous del1661A with patients having the other homo-
147 zygous/hemizygous mutations causing premature termination in the catalytic domain (Table 1). The average age of onset of BCC, SCC, and MM in patients with homozygous del1661A was 56, 63.7 and 67 years old, respectively, which were older than 47.2, 53.7, 48 in patients with C725G, G916T or C1066T. Furthermore, XP17KO, a younger sister of XP14KO with homozygous del1661A, has no skin cancer at the age of 61. It could be possible that patients having mutations outside the catalytic domain is less susceptible to skin cancers in comparison with those having mutations inside the catalytic domain, although we have to be careful to draw a conclusion since the development of skin cancer is very much influenced by the accumulative sun exposure. Additional factors other than the POLH gene might be also related with the development of skin cancer and might cause some heterogeneity within the same genotype. Broughton et al. reported that he could not find any genotype—phenotype relationship, although there were a few cases for each genotype [5]. We need more patients to draw a definite conclusion. MED was determined for 20 patients (Table 1) by standard phototesting [10] using FL32SE-30 sunlamps. Normal MED range for Japanese in our institution fall into 60—140 mJ/cm2. MED for our patients we could examined were all within normal range, which is consistent with clinical information that few patients experienced severe sunburn and their only signs were freckles before the age of 10. All patients grew up without protection from sunlight. Taken together, slight freckles on the sunexposed area, like XP9KO, can be the only clue to diagnose XP-V in their childhood. Combination of IP analysis of POLH protein and detection of these founder mutations in the POLH gene is a very useful method for genetic diagnosis for Japanese XP-V patients, especially for young patients, whose clinical features are not fully developed.
References [1] Hirai Y, Kodama Y, Moriwaki S, Noda A, Cullings HM, MacPhee DG, et al. Heterozygous individuals bearing a founder mutation in the XPA DNA repair gene comprise nearly 1% of the Japanese population. Mutat Res 2006;601:171—8. [2] Moriwaki S, Kraemer KH. Xeroderma pigmentosum–—bridging a gap between clinic and laboratory. Photodermatol Photoimmunol Photomed 2001;17:47—54. [3] Masutani C, Kusumoto R, Yamada A, Dohmae N, Yokoi M, Yuasa M, et al. The XPV (xeroderma pigmentosum variant) gene encodes human DNApolymerase eta. Nature 1999;399: 700— 4. [4] Johnson RE, Kondratick CM, Prakash S, Prakash L. hRAD30 mutations in the variant form of Xeroderma pigmentosum. Science 1999;285:263—5.
148
Letters to the Editor
[5] Broughton BC, Cordnonnier A, Kleijer WJ, Jaspers NG, Fawcett H, Raams A, et al. Molecular analysis of mutations in DNA polymerase eta in xeroderma pigmentosum-variant patients. Proc Natl Acad Sci 2002;99:815—20. [6] Gratchev A, Strein P, Utikal J, Goerdt S. Molecular genetics of xeroderma pigmentosum variant. Exp Dermatol 2003;12: 529—36. [7] Tanioka M, Masaki T, Ono R, Nagano T, Otoshi-Honda E, Matsumura Y, et al. Molecular analysis of DNA polymerase eta gene in Japanese patients diagnosed as xeroderma pigmentosum variant type. J Invest Dermatol 2007;127: 1745—51. [8] Nishigori C, Moriwaki S, Takebe H, Tanaka T, Imamura S. Gene alterations and clinical characteristics of xeroderma pigmentosum group A patients in Japan. Arch Dermatol 1994;130:191—7. [9] Masutani C, Araki M, Yamada A, Kusumoto R, Nogimori T, Maekawa T, et al. Xeroderma pigmentosum variant correcting protein from Hela cells has a thymine dimmer bypass DNA polymerase activity. EMBO J 1999;18:3491—501. [10] Baron ED, Stern RS. Correlating skin type and minimal erythema dose. Arch Dermatol 1999;135:1278—9.
Taro Masaki Ryusuke Ono Division of Dermatology, Graduate School of Medicine, Kobe University, Kobe, Japan
Miki Tanioka Department of Dermatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan Yoko Funasaka Tohru Nagano Division of Dermatology, Graduate School of Medicine, Kobe University, Kobe, Japan Shinichi Moriwaki Department of Dermatology, Osaka Medical College, Osaka, Japan Chikako Nishigori* Division of Dermatology, Graduate School of Medicine, Kobe University, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan *Corresponding author. Tel.: +81 78 382 6134; fax: +81 78 382 6149 E-mail address: [email protected] (C. Nishigori) 13 February 2008 doi:10.1016/j.jdermsci.2008.07.001
Available online at www.sciencedirect.com
Letters to the Editor
LETTER TO THE EDITOR Four types of possible founder mutations are responsible for 87% of Japanese patients with Xeroderma pigmentosum variant type KEYWORDS Xeroderma pigmentosum variant type; Hot spots; Immunoprecipitation; Minimum erythema dose
Xeroderma pigmentosum (XP) is classified into nucleotide excision repair (NER) deficient types, A through G, as well as a variant type. XP-variant (XPV, OMIN: 278750) is characterized by late onset of clinical skin symptoms such as skin cancers. XP-V cells show proficient NER but display an exaggerated delay in the recovery of the replicative DNA synthesis after UV irradiation. XP occurs at higher frequency in Japan (1:22,000) [1] than in the United States (1:250,000) [2]. Approximately 50% of all Japanese patients with XP are assigned to XP-A and 25% to XP-V [2]. The responsible gene for XP-V was cloned and its
product was identified as DNA polymerase eta (POLH, Genebank accession number NM006502), which enables cells to synthesize the correct daughter strands, despite the presence of thymidine dimers, onto the UV-damaged template DNA [3,4]. After the cloning of POLH, genetic analysis revealed many mutation sites in the POLH gene in patients with XP-V [5—7]. We previously reported that an immunoprecipitation (IP) analysis with antiPOLH antibodies is a useful method for screening patients suspected of XP-V, showing clear coincidence between the molecular defect in the POLH gene and its protein loss [7], although this method has limitation that miss mis-sense mutation which generate a stable but non-functional protein. In this study after obtaining written informed consent, additional 13 Japanese patients were diagnosed as XP-V by IP analysis and POLH mutations were identified for those patients without 83 kDa POLH protein band. We combined 13 XP-V patients in this study together with 14 XP-V patients in our previous study [7] and analyzed both mutation frequency among Japanese patients (Fig. 1) and genotype—
Fig. 1 Mutation sites and its frequency of POLH gene in Japanese XP-V patients. (a) The mutation sites and the number of patients are indicated. ‘‘Homo’’ stands for homozygous mutation and ‘‘Hetero’’ stands for heterozygous mutation. As for the possible founder mutations, the allele frequencies were indicated. (b) Genotype and its predicted POLH protein. NLS stands for nuclear localization signal.
Cell strain
Age
Genotype
Amino acid changes
IP band
UDS (%)
Age onset of skin cancers BCC
SCC
MM
45
52 45
Homozygous/Hemizygous nonsense mutation XPV6HM d 53 C725G S 242 stop XPV4KO d 55 C725G S 242 stop XPV11HM d 69 G916T E 306 stop XPV10KO 62 G916T E 306 stop XPV6KO d 55 G916T E 306 stop XPV3 TK 69 G916T E 306 stop
Absent Absent Absent Absent Absent Absent
75 72 70 ND 92 89
37 45 59 41
Homozygous nonsense mutation XPV8KO 50 G916T XPV2HM d 68 C1066T
Absent Absent
ND 87
44 57
48
47.2
53.7
E 306 stop R 356 stop
C725G, G916T, C1066T average Homozygous/Hemizygous deletion XPV12HM d 43 del1661A XPV9KO
13
del1661A
XPV14KO e
71
del1661A
XPV17KO e
61
del1661A
Homozygous deletion XPV11KO 79 del1661A XPV13KO
67
del1661A
Absent
66
Absent
92
Absent
90—100
Absent
89.35
554 frameshift stop at 584 554 frameshift stop at 584
Absent
57.2
76
Absent
83
36
del1661A average Homozygous/ Hemizygous splicing mutation 54 G490T Frameshift or XPV7HM d large deletion# XPV10HM d 67 G490T Frameshift or large deletion# XPV12KO 49 G490T Frameshift or large deletion#
a
MED (mJ/cm2)
51
100 150 WNR
44 Multiple
150
—
136
Freckles
7—8 6—7
c
— — ND — — — + +
48
No Skin Cancers 71 No Skin Cancers
77 67 57.0
Consanguinity b
10
43
56
Sunburn
ND — ND — — ND
54 68
554 frameshift stop at 584 554 frameshift stop at 584 554 frameshift stop at 584 554 frameshift stop at 584
Photosensitivity
Letters to the Editor
Table 1 Genotype and phenotype in Japanese patients with XP-V
ND
ND
100
—
—
100
+
—
100
—
—
60
—
>116
—
14
+ +
67
Absent
115
47
—
6
ND
Absent
105
47
ND
13
ND
Absent
65
48
—
4
—
80
145
146
Table 1 (Continued )
Cell strain
Age
Genotype
Amino acid changes
IP band
UDS (%)
Age onset of skin cancers BCC
XPV15KO
28
G490T
XPV1TK
75
G490T
Homozygous splicing mutation 82 G490T XPV1HM d XPV2KO d
69
G490T
XPV5KO d
57
G490T
XPV2 TK
28
G490T/C1066T
MED (mJ/cm2)
Sunburn
Consanguinity b
Freckles
110
27
80
—
Absent
89
73
WNR
ND
Frameshift or large deletion# Frameshift or large deletion# Frameshift or large deletion#
Absent
109
71
57
120
+
7
+
Absent
91
22
45
60
—
5
+
Absent
75
45
70
+
7
+
56
WNR
NS
35
WNR 100
ND — —
24
WNR
ND
A117P
Faint
88
S 242 stop + K589T S 242 stop + K589T Frameshift or large deletion# + E 306 stop Frameshift or large deletion# + R 356 stop
Absent Absent Absent
96 ND 108
Absent
ND
Multiple 35 24
7
c
Absent
48.25
Compound heterozygote XPV8HM d 39 C725G/A1766C XPV16KO 35 C725G/A1766C XPV1KO d 34 G490T/G916T
MM
a
Frameshift or large deletion# Frameshift or large deletion#
G490T average Homozygous missense mutation XPV3KO d 50 G349C
SCC
Photosensitivity
— —
48.2 + 15 13 13
— — — —
Letters to the Editor
BCC: Basal cell carcinoma, SCC: Squamous cell carcinoma, MM: Malignant melanoma, NS: not specified, WNR: within normal range in terms of the institution standard, IP: immunoprecipitation, ND: no data. a MED for normal Japanese are between 60 and 140 mJ/cm2. b Experience of severe sunburn in their childhood according to patient’s history. c Age onset freckles on the sun-exposed area were indicated d Mutations for these patients are reported in ref. [7]. e Siblings. # 164 frameshift stop at 192, deletion from G-134 to K-163.
Letters to the Editor phenotype relationship (Table 1). Previously, we have reported that G490T was a possible hot spot. Here, we identified del1661A is the second most frequent mutation. Eighteen (33%) out of 54 alleles (27 patients) were G490T, 12 (22%) were del1661A, 11 (20%) were G916T and 6 (11%) were C725G. These four types of mutations were responsible for 47 (87%) out of 54 mutated alleles of Japanese patients with XP-V (Fig. 1a). Among Japanese XP-A patients, founder mutation has been indicated, where one particular type of mutation was detected in high frequency (85%) [1,8]. In XP-V also we identified four types of possible founder mutations, namely G490T, del1661A, G916T and C725G. Among 27 patients, 8 patients had consanguinity. Since XPV3KO is the only patient with homozygous G349C and his parents are second cousin, G349 C might be infrequent. Because most patients did not have consanguinity and all patients except XP14KO and XP17KO are not related and their origin were diverse, it could be possible that these mutations are not founder mutations but hot spots. However considering that all these mutations were not reported in countries other than Japan so far (Fig. 1a), it is likely that these mutations arose in Japan long time ago and spread over here. Two unrelated patients, XPV16KO in this study and XPV8HM [7] in the previous study, showed the same type of compound heterozygotes, C725G and A1766C. Although we have already confirmed a missense mutation A1766C is not a single nucleotide polymorphism [7], the second case of this type of compound heterozygote reconfirmed that A1766C should be the cause of the disease. The POLH protein consists of 713 amino acids and its polymerase activity resides entirely in the first 511 sequence [9], containing highly conserved among damage bypass replication proteins (Fig. 1b). We assessed genotype—phenotype relationships, by comparing clinical features including minimal erythema dose (MED), sun-induced freckles, age onset of skin cancers and repair ability in relation to the predicted amino acids (Fig. 1). Clinical features were summarized and arranged according to the genotype (Table 1). Unscheduled DNA synthesis levels were not significantly different among different genotypes. All patients except for XPV9KO and XPV17KO developed skin cancers. Among homozygous/hemizygous mutations detected, del1661A mutations cause frameshift at codon 554, which results in termination at codon 584 outside the catalytic domain, whereas C725G, G916T and C1066T cause a termination codon inside the catalytic domain. Thus, we compared clinical features of 6 patients having homozygous/hemizygous del1661A with patients having the other homo-
147 zygous/hemizygous mutations causing premature termination in the catalytic domain (Table 1). The average age of onset of BCC, SCC, and MM in patients with homozygous del1661A was 56, 63.7 and 67 years old, respectively, which were older than 47.2, 53.7, 48 in patients with C725G, G916T or C1066T. Furthermore, XP17KO, a younger sister of XP14KO with homozygous del1661A, has no skin cancer at the age of 61. It could be possible that patients having mutations outside the catalytic domain is less susceptible to skin cancers in comparison with those having mutations inside the catalytic domain, although we have to be careful to draw a conclusion since the development of skin cancer is very much influenced by the accumulative sun exposure. Additional factors other than the POLH gene might be also related with the development of skin cancer and might cause some heterogeneity within the same genotype. Broughton et al. reported that he could not find any genotype—phenotype relationship, although there were a few cases for each genotype [5]. We need more patients to draw a definite conclusion. MED was determined for 20 patients (Table 1) by standard phototesting [10] using FL32SE-30 sunlamps. Normal MED range for Japanese in our institution fall into 60—140 mJ/cm2. MED for our patients we could examined were all within normal range, which is consistent with clinical information that few patients experienced severe sunburn and their only signs were freckles before the age of 10. All patients grew up without protection from sunlight. Taken together, slight freckles on the sunexposed area, like XP9KO, can be the only clue to diagnose XP-V in their childhood. Combination of IP analysis of POLH protein and detection of these founder mutations in the POLH gene is a very useful method for genetic diagnosis for Japanese XP-V patients, especially for young patients, whose clinical features are not fully developed.
References [1] Hirai Y, Kodama Y, Moriwaki S, Noda A, Cullings HM, MacPhee DG, et al. Heterozygous individuals bearing a founder mutation in the XPA DNA repair gene comprise nearly 1% of the Japanese population. Mutat Res 2006;601:171—8. [2] Moriwaki S, Kraemer KH. Xeroderma pigmentosum–—bridging a gap between clinic and laboratory. Photodermatol Photoimmunol Photomed 2001;17:47—54. [3] Masutani C, Kusumoto R, Yamada A, Dohmae N, Yokoi M, Yuasa M, et al. The XPV (xeroderma pigmentosum variant) gene encodes human DNApolymerase eta. Nature 1999;399: 700— 4. [4] Johnson RE, Kondratick CM, Prakash S, Prakash L. hRAD30 mutations in the variant form of Xeroderma pigmentosum. Science 1999;285:263—5.
148
Letters to the Editor
[5] Broughton BC, Cordnonnier A, Kleijer WJ, Jaspers NG, Fawcett H, Raams A, et al. Molecular analysis of mutations in DNA polymerase eta in xeroderma pigmentosum-variant patients. Proc Natl Acad Sci 2002;99:815—20. [6] Gratchev A, Strein P, Utikal J, Goerdt S. Molecular genetics of xeroderma pigmentosum variant. Exp Dermatol 2003;12: 529—36. [7] Tanioka M, Masaki T, Ono R, Nagano T, Otoshi-Honda E, Matsumura Y, et al. Molecular analysis of DNA polymerase eta gene in Japanese patients diagnosed as xeroderma pigmentosum variant type. J Invest Dermatol 2007;127: 1745—51. [8] Nishigori C, Moriwaki S, Takebe H, Tanaka T, Imamura S. Gene alterations and clinical characteristics of xeroderma pigmentosum group A patients in Japan. Arch Dermatol 1994;130:191—7. [9] Masutani C, Araki M, Yamada A, Kusumoto R, Nogimori T, Maekawa T, et al. Xeroderma pigmentosum variant correcting protein from Hela cells has a thymine dimmer bypass DNA polymerase activity. EMBO J 1999;18:3491—501. [10] Baron ED, Stern RS. Correlating skin type and minimal erythema dose. Arch Dermatol 1999;135:1278—9.
Taro Masaki Ryusuke Ono Division of Dermatology, Graduate School of Medicine, Kobe University, Kobe, Japan
Miki Tanioka Department of Dermatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan Yoko Funasaka Tohru Nagano Division of Dermatology, Graduate School of Medicine, Kobe University, Kobe, Japan Shinichi Moriwaki Department of Dermatology, Osaka Medical College, Osaka, Japan Chikako Nishigori* Division of Dermatology, Graduate School of Medicine, Kobe University, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan *Corresponding author. Tel.: +81 78 382 6134; fax: +81 78 382 6149 E-mail address: [email protected] (C. Nishigori) 13 February 2008 doi:10.1016/j.jdermsci.2008.07.001
Available online at www.sciencedirect.com