- Email: [email protected]
Novel compound heterozygous mutations in CTSC gene cause Papillon–Lefèvre syndrome with high serum immunoglobulin E
258
Letters to the Editor / Journal of Dermatological Science 76 (2014) 255–271
Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.jdermsci. 2014.08.015. References [1] Suenaga M. Genetical studies on skin diseases. VII. Dyschromatosis universalis hereditaria in five generations. Tohoku J Exp Med 1952;55:373–6. [2] Urabe K, Hori Y, Dyschromatosis. Semin Cutan Med Surg 1997;16:81–5. [3] AI Hawsawi K, Al Aboud K, Ramesh V, Al Aboud D. Dyschromatosis universalis hereditaria: report of a caseand review of the literature. Pediatr Dent 2002;19:523–6. [4] Xing QH, Wang MT, Chen XD, Feng GY, Ji HY, Yang JD, et al. A gene locus responsible for dyschromatosis symmtrica hereditaria (DSH) maps to chromosome 6q24.2–q25.2. Am J Hum Genet 2003;73:377–82. [5] Stuhrmann M, Hennies HC, Bukhari IA, Brakensiek K, Nu¨rnberg G, Becker C, et al. Dyschromatosis universalis hereditaria: evidence for autosomal recessive inheritance and identification of a new locus on chromosome 12q21–q23. Clin Genet 2008;73:566–72. [6] Zhang C, Li Duanzhuo, Zhang J, Chen X, Huang M, Archacki S, et al. Mutations in ABCB6 cause dyschromatosis universalis hereditaria. J Invest Dermatol 2013;133(9):2221–8. [7] Cui YX, Xia XY, Zhou Y, Gao L, Shang XJ, Ni T, et al. Novel mutations of ABCB6 associated with autosomaldominant dyschromatosis universalis hereditaria. PLoS ONE 2013;8(11):e79808. [8] Liu H, Li Y, Hung KK, Wang N, Wang C, Chen X, et al. Genome-wide linkage, exome sequencing and functional analyses identify ABCB6 as the pathogenic gene of dyschromatosis universalis hereditaria. PLoS ONE 2014;9(2):e87250. [9] Andolfo I, Alper SL, Delaunay J, Auriemma C, Russo R, Asci R, et al. Missense mutations in the ABCB6 transporter cause dominant familial pseudohyperkalemia. Am J Hematol 2013;88(1):66–72. [10] Wang L, He F, Bu J, Zhen Y, Liu X, Du W, et al. ABCB6 mutations cause ocular coloboma. Am J Hum Genet 2012;90(1):40–8.
Chaoxia Lua,1, Jie Liub,1, Fang Liua, Yaping Liua, Donglai Mab,*, Xue Zhanga,** a McKusick-Zhang Center for Genetic Medicine, State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine Peking Union Medical College, Beijing 100005, China; bDepartment of Dermatology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100073, China *Corresponding author at: Department of Dermatology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, 1 shuai fu yuan, Beijing 100073, China. Tel.: +86 10 69151536 **Corresponding author at: Center for Genetic Medicine, State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine Peking Union Medical College, 5 Dong Dan San Tiao, New Bldg., Room 716, Beijing 100005, China. Tel.: +86 10 65105110 E-mail addresses: [email protected] (D. Ma), [email protected] (X. Zhang). 1
These authors contributed equally to this work.
Received 28 May 2014 http://dx.doi.org/10.1016/j.jdermsci.2014.08.015
Letter to the Editor Novel compound heterozygous mutations in CTSC gene cause Papillon–Lefe`vre syndrome with high serum immunoglobulin E Dear Editor, Papillon–Lefe`vre syndrome (PLS; OMIM: 245000) is an extremely rare autosomal recessive condition characterized by palmoplantar hyperkeratosis and periodontitis. PLS develops because of mutations in the cathepsin C gene (CTSC) located on chromosome 11q14.1-q21 [1]. To date, more than 70 mutations have been reported for the CTSC gene [2–4]. However, few PLS patients with high levels of serum immunoglobulin E (IgE) have been described in previous studies. Here, we report a compound heterozygous including two missense mutations in CTSC gene, leading to a typical phenotype in a Chinese patient with high serum IgE. A 24-year-old Chinese male was referred to our out-patient clinic with the chief complaint of a long history of hyperkeratosis and recurrent pyogenic skin infections. His parents recalled that he had severe periodontitis at the age of 2 years, resulting in total deciduous teeth loss before 4-year-old. The majority of his permanent teeth fell off by the age of 13 years. The family history revealed non-consanguineous marriage of the unaffected parents and he was the only affected one of the family. Dermatological examination revealed symmetric, well-demarcated, yellowish, keratotic plaques affecting the skin of his palms and soles and extending on to the dorsal surfaces (Fig. 1a–c). Sharply circumscribed, scaly and hyperpigmented patches regarded as tinea cruris appeared on the thighs (Fig. 1d). Superficial ulcers with purulent discharge and crusting on the legs were
evident (Fig. 1e). Additionally, there were numerous polymorphic scarring lesions on the buttocks, thighs and calves (Fig. 1d). Intraoral examination showed the majority of dentition was absent (Fig. 1f). Orthopantomography revealed severe absorption of the alveolar bone (Fig. 1g). Skin biopsy from his right ankle showed irregular hyperkeratosis, marked acanthosis and conspicuous perivascular lymphocytic and histiocytic infiltrates (Fig. 1h). Laboratory data obtained by blood chemistry tests showed IgE level was more than 3000 IU/mL (the normal value is 1.27 IU/mL– 241.3 IU/mL). The proportions of different lymphocyte subsets were determined in the peripheral blood of patient by flow cytometry technique. The results indicate the percent of T-cell (CD3+) was 47 (the normal value is 60–79) (Fig. 2a) and the percent of Th-cell (CD3+CD4+) was 26.7 (the normal value is 34–52) (Fig. 2a). Serum IFN-g and IL-4 levels in PLS patient and healthy individuals (n = 10) were also measured directly by ELISA assays. The serum level of IFN-g and IL-4 among patient and control groups were as follows respectively: 6.85 pg/mL versus 8.76 pg/mL (mean) and 39.48 pg/mL versus 17.51 pg/mL (mean) (Fig. 2b). Genomic DNA was isolated from peripheral blood leukocytes of patient and his clinically unaffected family members as well as unrelated controls (n = 50), and genetic analysis of CTSC was performed. Mutation analysis revealed compound heterozygous mutations including two missense changes: c.824C > T in exon 6 (Fig. 2c) and c.1040A > G in exon 7 (Fig. 2d). The former is a novel mutation which changed a threonine (ACC) to an isoleucine (ATC) at amino-acid position 275 (p.T275I), whereas the latter is a previously reported mutation which changed a tyrosine (TAT) to a cysteine (TGT) at amino-acid position 347 (p.Y347C). His father and mother were heterozygous for T275I and Y347C respectively.
Letters to the Editor / Journal of Dermatological Science 76 (2014) 255–271
259
Fig. 1. Well-demarcated, yellowish, keratotic, confluent plaques affecting the skin of his palms and soles and extending on to the dorsal surfaces (a–c); tinea cruris were seen on the thighs (d); superficial ulcers on the legs and psoriasiform lesions on the ankle (e); the majority of dentition were absent (f, g); skin biopsy showed hyperkeratosis, marked acanthosis and conspicuous perivascular lymphocytic and histiocytic infiltrates (HE10, h).
Fig. 2. Flow cytometry evaluation of the T-cell subsets in PLS patient indicated the percentage of T-cell (CD3+) was 47 and the percentage of Th-cell (CD3+CD4+) was 26.7 (a). Comparison of IFN-g and IL-4 in serum of PLS patient with controls (b). Sequence chromatograms revealed the patient was compound heterozygous mutations: c.824C > T in exon 6 and c.1040A > G in exon 7, his father and mother were heterozygous for c.824C > T and c.1040A > G respectively (c, d).
On the basis of clinical symptoms, histopathology and genetic analyses, we diagnosed this patient as Papillon–Lefe`vre syndrome (PLS) here. Compound heterozygous mutations were detected in our patient. To the best of our knowledge, exon 6 and exon
7 encode the heavy chain of the cathepsin C protein, which is thought to be important for enzyme activity. It is likely that such mutations would affect critical highly conserved amino acids and cause a conformational alteration that may decrease or abolish the
260
Letters to the Editor / Journal of Dermatological Science 76 (2014) 255–271
activity of the CTSC protein. These mutations will lead to inactivation of the encoded cysteine protease causing disregulation of the immune response, which could possibly explain the severe periodontitis and susceptibility to microbiology infections in PLS [5]. Wen et al. [6] also reported a Chinese Papillon–Lefe`vre syndrome patient with high IgE. However, the recurrent skin inflammation, dental abnormalities and extremely high serum IgE level reminded us of the hyper IgE syndrome (HIES). So the coding regions and flanking introns of TYK2 and DOCK8, as well as STAT3 gene contributing to HIES were also amplified. However, genetic analysis showed no mutations in genes related to HIES. Thus we speculated that dysfunction of cellular immunity may contribute to the secondary higher levels of serum IgE in this PLS patient. For our case, the percent of T-cell (CD3+) and Th-cell (CD3+CD4+) were below the normal limits, suggesting immunologic deficiencies. The serum level of IL-4 was significantly increased, whereas that of IFN-g was decreased in our patient with PLS compared to healthy controls might imply Th1/Th2 cytokine imbalance towards a Th2 bias. As is known to all that Th2 cells are a major source of IL-4 which plays a critical role in the induction of the IgE synthesis. While the Th1 cells produce IFN-g which inhibits the IL-4-induced IgE synthesis. Thus we speculated that an immune response towards the Th2 phenotype resulted in high serum IgE level in this PLS patient. However, the primary cellular source of IL-4 that skews an immune response towards the Th2 phenotype is not yet known. Up to now, more than 70 mutations have been detected in CTSC gene across various ethnic backgrounds. Most mutations were located in the exon 6 and exon 7 of CTSC gene of typical PLS patients [7]. In addition, There is a variant of late onset PLS that lack the CTSC mutations [8], suggesting that other genes might have similar functions to the CTSC gene on the skin and therefore compensating for its absence. Several reports showed that identical mutations in the CTSC gene can contribute to the development of PLS or Haim–Munk syndrome (HMS) [9] as well as prepubertal periodontitis (PPP) [10]. Phenotypic variants associated with the CTSC mutation may reflect the influence of additional genetic or environmental factors. Further mutational investigations are required to better understand the relationship between the genotypes and phenotypes of patients with PLS. Acknowledgements
References [1] Toomes C, James J, Wood AJ, Wu CL, McCormick D, Lench N, et al. Loss-offunction mutations in the cathepsin C gene result in periodontal disease and palmoplantar keratosis. Nat Genet 1999;23:21–4. [2] Nagy N, Va´lyi P, Csoma Z, Sula´k A, Tripolszki K, Farkas K, et al. CTSC and Papillon–Lefe`vre syndrome: detection of recurrent mutations in Hungarian patients, a review of published variants and database update. Mol Genet Genomics 2014. http://dx.doi.org/10.1002/mgg3.61. [3] Kobayashi T, Sugiura K, Takeichi T, Akiyama M. The novel CTSC homozygous nonsense mutation p.Lys106X in a patient with Papillon–Lefe`vre syndrome with all permanent teeth remaining at over 40 years of age. Br J Dermatol 2013;169:948–50. [4] Ochiai T, Nakano H, Rokunohe D, Akasaka E, Toyomaki Y, Mitsuhashi Y, et al. Novel p.M1T and recurrent p.G301S mutations in cathepsin C in a Japanese patient with Papillon–Lefe`vre syndrome: implications for understanding the genotype/phenotype relationship. J Dermatol Sci 2009;53:73–5. [5] Nakano A, Nomura K, Nakano H, Ono Y, LaForgia S, Pulkkinen L, et al. Papillon– Lefe`vre syndrome: mutations and polymorphisms in the cathepsin C gene. J Investig Dermatol 2001;116:339–43. [6] Wen X, Wang X, Duan X. High immunoglobulin E in a Chinese Papillon–Lefe`vre syndrome patient with novel compound mutations of cathepsin C. J Dermatol 2012;39:664–5. [7] Lefe`vre C, Blanchet-Bardon C, Jobard F, Bouadjar B, Stalder JF, Cure S, et al. Novel point mutations, deletions, and polymorphisms in the cathepsin C gene in nine families from Europe and North Africa with Papillon–Lefevre syndrome. J Investig Dermatol 2001;117:1657–61. [8] Pilger U, Hennies HC, Truschnegg A, Aberer El. Late-onset Papillon–Lefevre syndrome without alteration of the cathepsin C gene. J Am Acad Dermatol 2003;5:S240–3. [9] Rai R, Thiagarajan S, Mohandas S, Natarajan K, Shanmuga Sekar C, Ramalingam S. Haim Munk syndrome and Papillon Lefevre syndrome – allelic mutations in cathepsin C with variation in phenotype. Int J Dermatol 2010;49:541–3. [10] Hewitt C, McCormick D, Linden G, Turk D, Stern I, Wallace I, et al. The role of cathepsin C in Papillon–Lefe`vre syndrome, prepubertal periodontitis, and aggressive periodontitis. Hum Mutat 2004;23:222–8.
Zhiming Li1,*, Jingjing Liu1, Shan Fang, Haigang Zhu, Xueqi Zhang, Jianfeng Cai, Bingxu Li, Yunsheng Xu Department of Dermatology and Venereology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China *Corresponding author E-mail addresses: [email protected] (Z. Li), [email protected] (Y. Xu). 1
We are grateful to all the family for their participation in the study. This work is supported by the National Natural Scientific Fund (81272987), and Zhejiang Provincial Natural Science Foundation of China (LY12H11011).
Co-first author.
Received 24 April 2014 http://dx.doi.org/10.1016/j.jdermsci.2014.09.009
Letter to the Editor Oculocutaneous albinism (OCA) in Colombia: First molecular screening of the TYR and OCA2 genes in South America
Keywords: Oculocutaneous albinism; TYR gene; OCA2 gene; Colombia; South America
Oculocutaneous albinism (OCA) is a group of autosomal recessive disorders of the melanin biosynthesis pathway, characterized by complete lack or generalized reduction in pigmentation
of hair, skin and eyes [1]. Individuals affected by OCA are at high risk of ultraviolet (UV) radiation-induced skin cancer due to the lack of photoprotective melanin. In addition, reduced visual acuity is observed mainly because early melanin precursors are vital for normal visual development in mammalian embryogenesis [2]. Genetically, seven nonsyndromic types of OCA have been described, OCA1-OCA 7 [3]. OCA1A (MIM #203100), the most common and severe form known is caused by mutations in TYR (MIM *606933) gene whereas OCA2 (MIM #203200), is a milder phenotype and the second most common type of OCA caused by mutations in OCA2 (MIM *611409) gene [4]. It is estimated that 80% of worldwide cases of OCA are explained by mutations in these two genes, TYR and OCA2, accounting for 50% and 30% cases respectively [5]. Here, we
Letters to the Editor / Journal of Dermatological Science 76 (2014) 255–271
Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.jdermsci. 2014.08.015. References [1] Suenaga M. Genetical studies on skin diseases. VII. Dyschromatosis universalis hereditaria in five generations. Tohoku J Exp Med 1952;55:373–6. [2] Urabe K, Hori Y, Dyschromatosis. Semin Cutan Med Surg 1997;16:81–5. [3] AI Hawsawi K, Al Aboud K, Ramesh V, Al Aboud D. Dyschromatosis universalis hereditaria: report of a caseand review of the literature. Pediatr Dent 2002;19:523–6. [4] Xing QH, Wang MT, Chen XD, Feng GY, Ji HY, Yang JD, et al. A gene locus responsible for dyschromatosis symmtrica hereditaria (DSH) maps to chromosome 6q24.2–q25.2. Am J Hum Genet 2003;73:377–82. [5] Stuhrmann M, Hennies HC, Bukhari IA, Brakensiek K, Nu¨rnberg G, Becker C, et al. Dyschromatosis universalis hereditaria: evidence for autosomal recessive inheritance and identification of a new locus on chromosome 12q21–q23. Clin Genet 2008;73:566–72. [6] Zhang C, Li Duanzhuo, Zhang J, Chen X, Huang M, Archacki S, et al. Mutations in ABCB6 cause dyschromatosis universalis hereditaria. J Invest Dermatol 2013;133(9):2221–8. [7] Cui YX, Xia XY, Zhou Y, Gao L, Shang XJ, Ni T, et al. Novel mutations of ABCB6 associated with autosomaldominant dyschromatosis universalis hereditaria. PLoS ONE 2013;8(11):e79808. [8] Liu H, Li Y, Hung KK, Wang N, Wang C, Chen X, et al. Genome-wide linkage, exome sequencing and functional analyses identify ABCB6 as the pathogenic gene of dyschromatosis universalis hereditaria. PLoS ONE 2014;9(2):e87250. [9] Andolfo I, Alper SL, Delaunay J, Auriemma C, Russo R, Asci R, et al. Missense mutations in the ABCB6 transporter cause dominant familial pseudohyperkalemia. Am J Hematol 2013;88(1):66–72. [10] Wang L, He F, Bu J, Zhen Y, Liu X, Du W, et al. ABCB6 mutations cause ocular coloboma. Am J Hum Genet 2012;90(1):40–8.
Chaoxia Lua,1, Jie Liub,1, Fang Liua, Yaping Liua, Donglai Mab,*, Xue Zhanga,** a McKusick-Zhang Center for Genetic Medicine, State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine Peking Union Medical College, Beijing 100005, China; bDepartment of Dermatology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100073, China *Corresponding author at: Department of Dermatology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, 1 shuai fu yuan, Beijing 100073, China. Tel.: +86 10 69151536 **Corresponding author at: Center for Genetic Medicine, State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine Peking Union Medical College, 5 Dong Dan San Tiao, New Bldg., Room 716, Beijing 100005, China. Tel.: +86 10 65105110 E-mail addresses: [email protected] (D. Ma), [email protected] (X. Zhang). 1
These authors contributed equally to this work.
Received 28 May 2014 http://dx.doi.org/10.1016/j.jdermsci.2014.08.015
Letter to the Editor Novel compound heterozygous mutations in CTSC gene cause Papillon–Lefe`vre syndrome with high serum immunoglobulin E Dear Editor, Papillon–Lefe`vre syndrome (PLS; OMIM: 245000) is an extremely rare autosomal recessive condition characterized by palmoplantar hyperkeratosis and periodontitis. PLS develops because of mutations in the cathepsin C gene (CTSC) located on chromosome 11q14.1-q21 [1]. To date, more than 70 mutations have been reported for the CTSC gene [2–4]. However, few PLS patients with high levels of serum immunoglobulin E (IgE) have been described in previous studies. Here, we report a compound heterozygous including two missense mutations in CTSC gene, leading to a typical phenotype in a Chinese patient with high serum IgE. A 24-year-old Chinese male was referred to our out-patient clinic with the chief complaint of a long history of hyperkeratosis and recurrent pyogenic skin infections. His parents recalled that he had severe periodontitis at the age of 2 years, resulting in total deciduous teeth loss before 4-year-old. The majority of his permanent teeth fell off by the age of 13 years. The family history revealed non-consanguineous marriage of the unaffected parents and he was the only affected one of the family. Dermatological examination revealed symmetric, well-demarcated, yellowish, keratotic plaques affecting the skin of his palms and soles and extending on to the dorsal surfaces (Fig. 1a–c). Sharply circumscribed, scaly and hyperpigmented patches regarded as tinea cruris appeared on the thighs (Fig. 1d). Superficial ulcers with purulent discharge and crusting on the legs were
evident (Fig. 1e). Additionally, there were numerous polymorphic scarring lesions on the buttocks, thighs and calves (Fig. 1d). Intraoral examination showed the majority of dentition was absent (Fig. 1f). Orthopantomography revealed severe absorption of the alveolar bone (Fig. 1g). Skin biopsy from his right ankle showed irregular hyperkeratosis, marked acanthosis and conspicuous perivascular lymphocytic and histiocytic infiltrates (Fig. 1h). Laboratory data obtained by blood chemistry tests showed IgE level was more than 3000 IU/mL (the normal value is 1.27 IU/mL– 241.3 IU/mL). The proportions of different lymphocyte subsets were determined in the peripheral blood of patient by flow cytometry technique. The results indicate the percent of T-cell (CD3+) was 47 (the normal value is 60–79) (Fig. 2a) and the percent of Th-cell (CD3+CD4+) was 26.7 (the normal value is 34–52) (Fig. 2a). Serum IFN-g and IL-4 levels in PLS patient and healthy individuals (n = 10) were also measured directly by ELISA assays. The serum level of IFN-g and IL-4 among patient and control groups were as follows respectively: 6.85 pg/mL versus 8.76 pg/mL (mean) and 39.48 pg/mL versus 17.51 pg/mL (mean) (Fig. 2b). Genomic DNA was isolated from peripheral blood leukocytes of patient and his clinically unaffected family members as well as unrelated controls (n = 50), and genetic analysis of CTSC was performed. Mutation analysis revealed compound heterozygous mutations including two missense changes: c.824C > T in exon 6 (Fig. 2c) and c.1040A > G in exon 7 (Fig. 2d). The former is a novel mutation which changed a threonine (ACC) to an isoleucine (ATC) at amino-acid position 275 (p.T275I), whereas the latter is a previously reported mutation which changed a tyrosine (TAT) to a cysteine (TGT) at amino-acid position 347 (p.Y347C). His father and mother were heterozygous for T275I and Y347C respectively.
Letters to the Editor / Journal of Dermatological Science 76 (2014) 255–271
259
Fig. 1. Well-demarcated, yellowish, keratotic, confluent plaques affecting the skin of his palms and soles and extending on to the dorsal surfaces (a–c); tinea cruris were seen on the thighs (d); superficial ulcers on the legs and psoriasiform lesions on the ankle (e); the majority of dentition were absent (f, g); skin biopsy showed hyperkeratosis, marked acanthosis and conspicuous perivascular lymphocytic and histiocytic infiltrates (HE10, h).
Fig. 2. Flow cytometry evaluation of the T-cell subsets in PLS patient indicated the percentage of T-cell (CD3+) was 47 and the percentage of Th-cell (CD3+CD4+) was 26.7 (a). Comparison of IFN-g and IL-4 in serum of PLS patient with controls (b). Sequence chromatograms revealed the patient was compound heterozygous mutations: c.824C > T in exon 6 and c.1040A > G in exon 7, his father and mother were heterozygous for c.824C > T and c.1040A > G respectively (c, d).
On the basis of clinical symptoms, histopathology and genetic analyses, we diagnosed this patient as Papillon–Lefe`vre syndrome (PLS) here. Compound heterozygous mutations were detected in our patient. To the best of our knowledge, exon 6 and exon
7 encode the heavy chain of the cathepsin C protein, which is thought to be important for enzyme activity. It is likely that such mutations would affect critical highly conserved amino acids and cause a conformational alteration that may decrease or abolish the
260
Letters to the Editor / Journal of Dermatological Science 76 (2014) 255–271
activity of the CTSC protein. These mutations will lead to inactivation of the encoded cysteine protease causing disregulation of the immune response, which could possibly explain the severe periodontitis and susceptibility to microbiology infections in PLS [5]. Wen et al. [6] also reported a Chinese Papillon–Lefe`vre syndrome patient with high IgE. However, the recurrent skin inflammation, dental abnormalities and extremely high serum IgE level reminded us of the hyper IgE syndrome (HIES). So the coding regions and flanking introns of TYK2 and DOCK8, as well as STAT3 gene contributing to HIES were also amplified. However, genetic analysis showed no mutations in genes related to HIES. Thus we speculated that dysfunction of cellular immunity may contribute to the secondary higher levels of serum IgE in this PLS patient. For our case, the percent of T-cell (CD3+) and Th-cell (CD3+CD4+) were below the normal limits, suggesting immunologic deficiencies. The serum level of IL-4 was significantly increased, whereas that of IFN-g was decreased in our patient with PLS compared to healthy controls might imply Th1/Th2 cytokine imbalance towards a Th2 bias. As is known to all that Th2 cells are a major source of IL-4 which plays a critical role in the induction of the IgE synthesis. While the Th1 cells produce IFN-g which inhibits the IL-4-induced IgE synthesis. Thus we speculated that an immune response towards the Th2 phenotype resulted in high serum IgE level in this PLS patient. However, the primary cellular source of IL-4 that skews an immune response towards the Th2 phenotype is not yet known. Up to now, more than 70 mutations have been detected in CTSC gene across various ethnic backgrounds. Most mutations were located in the exon 6 and exon 7 of CTSC gene of typical PLS patients [7]. In addition, There is a variant of late onset PLS that lack the CTSC mutations [8], suggesting that other genes might have similar functions to the CTSC gene on the skin and therefore compensating for its absence. Several reports showed that identical mutations in the CTSC gene can contribute to the development of PLS or Haim–Munk syndrome (HMS) [9] as well as prepubertal periodontitis (PPP) [10]. Phenotypic variants associated with the CTSC mutation may reflect the influence of additional genetic or environmental factors. Further mutational investigations are required to better understand the relationship between the genotypes and phenotypes of patients with PLS. Acknowledgements
References [1] Toomes C, James J, Wood AJ, Wu CL, McCormick D, Lench N, et al. Loss-offunction mutations in the cathepsin C gene result in periodontal disease and palmoplantar keratosis. Nat Genet 1999;23:21–4. [2] Nagy N, Va´lyi P, Csoma Z, Sula´k A, Tripolszki K, Farkas K, et al. CTSC and Papillon–Lefe`vre syndrome: detection of recurrent mutations in Hungarian patients, a review of published variants and database update. Mol Genet Genomics 2014. http://dx.doi.org/10.1002/mgg3.61. [3] Kobayashi T, Sugiura K, Takeichi T, Akiyama M. The novel CTSC homozygous nonsense mutation p.Lys106X in a patient with Papillon–Lefe`vre syndrome with all permanent teeth remaining at over 40 years of age. Br J Dermatol 2013;169:948–50. [4] Ochiai T, Nakano H, Rokunohe D, Akasaka E, Toyomaki Y, Mitsuhashi Y, et al. Novel p.M1T and recurrent p.G301S mutations in cathepsin C in a Japanese patient with Papillon–Lefe`vre syndrome: implications for understanding the genotype/phenotype relationship. J Dermatol Sci 2009;53:73–5. [5] Nakano A, Nomura K, Nakano H, Ono Y, LaForgia S, Pulkkinen L, et al. Papillon– Lefe`vre syndrome: mutations and polymorphisms in the cathepsin C gene. J Investig Dermatol 2001;116:339–43. [6] Wen X, Wang X, Duan X. High immunoglobulin E in a Chinese Papillon–Lefe`vre syndrome patient with novel compound mutations of cathepsin C. J Dermatol 2012;39:664–5. [7] Lefe`vre C, Blanchet-Bardon C, Jobard F, Bouadjar B, Stalder JF, Cure S, et al. Novel point mutations, deletions, and polymorphisms in the cathepsin C gene in nine families from Europe and North Africa with Papillon–Lefevre syndrome. J Investig Dermatol 2001;117:1657–61. [8] Pilger U, Hennies HC, Truschnegg A, Aberer El. Late-onset Papillon–Lefevre syndrome without alteration of the cathepsin C gene. J Am Acad Dermatol 2003;5:S240–3. [9] Rai R, Thiagarajan S, Mohandas S, Natarajan K, Shanmuga Sekar C, Ramalingam S. Haim Munk syndrome and Papillon Lefevre syndrome – allelic mutations in cathepsin C with variation in phenotype. Int J Dermatol 2010;49:541–3. [10] Hewitt C, McCormick D, Linden G, Turk D, Stern I, Wallace I, et al. The role of cathepsin C in Papillon–Lefe`vre syndrome, prepubertal periodontitis, and aggressive periodontitis. Hum Mutat 2004;23:222–8.
Zhiming Li1,*, Jingjing Liu1, Shan Fang, Haigang Zhu, Xueqi Zhang, Jianfeng Cai, Bingxu Li, Yunsheng Xu Department of Dermatology and Venereology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China *Corresponding author E-mail addresses: [email protected] (Z. Li), [email protected] (Y. Xu). 1
We are grateful to all the family for their participation in the study. This work is supported by the National Natural Scientific Fund (81272987), and Zhejiang Provincial Natural Science Foundation of China (LY12H11011).
Co-first author.
Received 24 April 2014 http://dx.doi.org/10.1016/j.jdermsci.2014.09.009
Letter to the Editor Oculocutaneous albinism (OCA) in Colombia: First molecular screening of the TYR and OCA2 genes in South America
Keywords: Oculocutaneous albinism; TYR gene; OCA2 gene; Colombia; South America
Oculocutaneous albinism (OCA) is a group of autosomal recessive disorders of the melanin biosynthesis pathway, characterized by complete lack or generalized reduction in pigmentation
of hair, skin and eyes [1]. Individuals affected by OCA are at high risk of ultraviolet (UV) radiation-induced skin cancer due to the lack of photoprotective melanin. In addition, reduced visual acuity is observed mainly because early melanin precursors are vital for normal visual development in mammalian embryogenesis [2]. Genetically, seven nonsyndromic types of OCA have been described, OCA1-OCA 7 [3]. OCA1A (MIM #203100), the most common and severe form known is caused by mutations in TYR (MIM *606933) gene whereas OCA2 (MIM #203200), is a milder phenotype and the second most common type of OCA caused by mutations in OCA2 (MIM *611409) gene [4]. It is estimated that 80% of worldwide cases of OCA are explained by mutations in these two genes, TYR and OCA2, accounting for 50% and 30% cases respectively [5]. Here, we