- Email: [email protected]
Rothmund–Thomson Syndrome and Glomerulonephritis in a Homozygous C1q-Deficient Patient Due to a Gly164Ser C1qC Mutation
A Lo´pez-Lera et al. Rothmund–Thomson Syndrome and Glomerulonephritis
Connecticut, USA; 7Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut, USA; 8Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA and 9Pediatric Dermatology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA E-mail: [email protected] Work was done in New Haven, Connecticut, USA. SUPPLEMENTARY MATERIAL Supplementary material is linked to the online version of the paper at http://www.nature.com/jid
REFERENCES Fasano O, Aldrich T, Tamanoi F et al. (1984) Analysis of the transforming potential of the human H-ras gene by random mutagenesis. Proc Natl Acad Sci USA 81: 4008–12 Gripp KW, Lin AE (2012) Costello syndrome: a Ras/mitogen activated protein kinase pathway syndrome (rasopathy) resulting from
HRAS germline mutations. Genet Med 14: 285–92
Malumbres M, Barbacid M (2003) RAS oncogenes: the first 30 years. Nat Rev Cancer 3:459–65
Groesser L, Herschberger E, Ruetten A et al. (2012) Postzygotic HRAS and KRAS mutations cause nevus sebaceous and Schimmelpenning syndrome. Nat Genet 44:783–7
Moss C, Larkins S, Stacey M et al. (1993) Epidermal mosaicism and Blaschko’s lines. J Med Genet 30:752–5
Hafner C, Toll A, Gantner S et al. (2012) Keratinocytic epidermal nevi are associated with mosaic RAS mutations. J Med Genet 49:249–53
Peteiro C, Oliva NP, Zulaica A et al. (1989) Woolly-hair nevus: report of a case associated with a verrucous epidermal nevus in the same area. Pediatr Dermatol 6:188–90
Hafner C, Toll A, Real FX (2011) HRAS mutation mosaicism causing urothelial cancer and epidermal nevus. N Engl J Med 365: 1940–2
Shirley MD, Tang H, Gallione CJ et al. (2013) Sturge-Weber syndrome and port-wine stains caused by somatic mutation in GNAQ. N Engl J Med 368:1971–9
Harel S, Christiano AM (2012) Genetics of structural hair disorders. J Invest Dermatol 132:E22–6
Siegel DH, Mann JA, Krol AL et al. (2012) Dermatological phenotype in Costello syndrome: consequences of Ras dysregulation in development. Br J Dermatol 166:601–7
Levinsohn JL, Tian LC, Boyden LM et al. (2013) Whole-exome sequencing reveals somatic mutations in HRAS and KRAS, which cause nevus sebaceus. J Invest Dermatol 133: 827–30 Lindhurst MJ, Sapp JC, Teer JK et al. (2011) A mosaic activating mutation in AKT1 associated with the Proteus syndrome. N Engl J Med 365:611–9
Sun BK, Saggini A, Sarin KY et al. (2013) Mosaic activating RAS mutations in nevus sebaceus and nevus sebaceus syndrome. J Invest Dermatol 133:824–7 Venugopal V, Karthikeyan S, Gnanaraj P et al. (2012) Woolly hair nevus: a rare entity. Int J Trichology 4:42–3
Rothmund–Thomson Syndrome and Glomerulonephritis in a Homozygous C1q-Deficient Patient Due to a Gly164Ser C1qC Mutation Journal of Investigative Dermatology (2014) 134, 1152–1154; doi:10.1038/jid.2013.444; published online 21 November 2013
TO THE EDITOR Rothmund–Thomson syndrome (RTS; MIM#268400) is an autosomal recessive genodermatosis presenting in infancy with poikiloderma and heterogeneous clinical features including short stature, sparse scalp hair, sparse or absent eyelashes and/or eyebrows, juvenile cataracts, skeletal abnormalities, radial ray defects, premature aging, and a predisposition to osteosarcoma (Larizza et al., 2010). Approximately 60–65% of RTS patients carry deleterious mutations in the helicase gene RECQL4 (RTS-type II), predominantly exhibiting poikiloderma, congenital bone defects, and an increased risk of osteosarcoma. The remaining cases, characterized by poikiloderma, ectodermal dysplasia, and juvenile cataracts are negative for the
RECQL4-mutation scan (RTS-type I). At the present time, the cause of RTS-type I is unknown. C1q is the central pattern-recognition molecule in the classical pathway of the complement system. Mutations causing quantitative or functional deficiency of C1q (MIM#613652) have been associated with susceptibility to severe infections, autoimmune disease frequently including systemic lupus erythematosus or overlapping clinical entities, and glomerulonephritis (Botto et al., 1998; Roumenina et al., 2011; Schejbel et al., 2011). Here we report novel and follow-up data on the case of a 40-year-old man belonging to an already published Spanish family (Leyva-Cobia´n et al., 1981) in which three siblings were homozygous
Abbreviations: RECQL4, RecQ protein-like 4; RTS, Rothmund–Thomson syndrome Accepted article preview online 24 October 2013; published online 21 November 2013
1152 Journal of Investigative Dermatology (2014), Volume 134
C1q deficient and presented with renal abnormalities and diffuse glomerular deposits of IgM and C3 compatible with mesangial proliferative glomerulonephritis. Before the age of 12 years, the two boys and a girl also developed oculocutaneus manifestations, poikiloderma, and bilateral cataracts, characteristics compatible with RTS. Both parents and three additional siblings exhibited partial C1q deficiency and remained healthy with no sign of RTS affectation. Studies have been conducted in the only survivor from the pedigree originally published by Leyva-Cobia´n et al. (1981) that provide new data on this unusual case. Clinical features in the patient at diagnosis included macular erythema, erosive skin lesions on the face and finger tips, and bilateral capsular posterior cataracts. At present, he has not developed osteosarcoma or other malignancies.
A Lo´pez-Lera et al. Rothmund–Thomson Syndrome and Glomerulonephritis
Anti-C1QA mAbs Anti-C1QC mAbs Anti-C1Q pAbs A-B (55 kDa) 490 P163
G164
495 L165
C-C (41 kDa)
Mild reduction
A (32 kDa)
Wild type
C (27 kDa) c.490G>A
P163
490 S164 C1q-deficient
495 L165
Full reduction
Single chains C1Q NHP P
C1Q NHP P
C1Q NHP
P
Figure 1. Biochemical and molecular studies in a C1q-deficient individual affected by Rothmund– Thomson syndrome (RTS). (a) Chromatogram showing the homozygous c.490G4A missense mutation in the C1qC gene’s exon 3 of the propositus. (b) C1q was analyzed by western blotting of either normal human plasma (NHP), fresh plasma from the C1q-deficient propositus (P), and purified C1q (C1q) with anti-C1qA mAbs (left column), anti-C1qC mAbs (central column), and anti-C1q pAbs (right column). Each blot was replicated under mild reducing and nonreducing conditions, allowing the detection of the full molecule, A-B and C-C dimers, or A and C single chains. The specific band in the reduced anti-C1qC blot is indicated by a black arrow.
To further characterize his complex phenotype, we carried out PCR amplification and direct sequencing of the C1q-A, -B, -C, and RECQL4 genes, together with a new measurement of the C1q circulating levels, which assessed total absence of the protein in plasma. Examination of the full coding and flanking intronic sequences of the C1q gene cluster on chromosome 1 revealed the homozygous, unreported c.490G4A (Gly164Ser) mutation in the third exon of the C1QC gene (Figure 1a). The glycine residue affected by this previously unreported mutation is adjacent to one of the six hydrophobic patches that define the interfaces among the A-, B-, and C-chains within the globular head (Gaboriaud et al., 2003). Therefore, the substitution of a nonpolar glycine by a bigger and more polar serine residue in such position probably has profound structural implications abolishing either multimerization or secretion of the molecule. Both parents and the remaining siblings were all heterozygous for the mutation. Western blotting of the patient’s circulating C1q with either polyclonal anti-C1q antibodies (C1q pAbs) or mAbs directed against the C1q-A (C1q-A mAbs) and -C (C1q-C mAbs) chains confirmed total absence of the full C1q molecule and also of circulating complexes between A-B and C-C chains in the plasma of the propositus (Figure 1b). No mutation was found in the 21 exons and exon–intron boundaries of the RECQL4 gene on chromosome 8,
thus defining the patient as RTS-type I, which is in good agreement with his pathological condition, predominantly characterized by oculocutaneous affectation. DISCUSSION The co-occurrence of glomerular disease and genodermatosis inherited in an apparent dominant manner is rare but not unique. The phenotypic abnormalities seen in the family presented here resemble some characteristics already reported by Sherwood et al. (1987) in a father-and-son cohort affected by glomerulonephritis and an unusual skin disease resembling RTS. In that case, however, the activity of the classical complement pathway as measured by CH50 hemolytic assay and serum levels of C3 and C4 were all normal, discarding a homozygous defect of C1q. Studies conducted in animal models have also shown that mice lacking DNA topoisomerase III beta, an enzyme interacting with helicases of the RecQ family such as BLM (causative gene of human Bloom progeroid syndrome), develop a complex phenotype, which includes hypertrophy of the spleen and submandibular lymph nodes, glomerulonephritis, and perivascular infiltrates in various organs (Kwan and Wang, 2001). Such a complex phenotype underscores the pleiotropic effects associated with the deregulation of DNA topological maintenance pathways and opens the possibility that genes involved in such pathways could have a role in the development of RTS-type I.
With the present data, the strict coinheritance of the C1q deficiency and RTS traits observed in this cohort suggests the presence of one or several dominant sequence variations in linkage disequilibrium with the C1q locus as a cause for the RTS-type I phenotype in the family. Alternatively, homozygous C1q deficiency could act as a diseasemodifying factor for RTS in the presence of an additional, undescribed mutation in an autosomal chromosome. Written, informed consent from the patients and approval from the research ethics committee of Hospital Universitario La Paz were obtained in order to carry out these studies. CONFLICT OF INTEREST The authors state no conflict of interest.
ACKNOWLEDGMENTS We are indebted to Dr F Leyva-Cobia´n (Valdecilla Hospital, Santander, Spain) for his helpful discussion on the patient and his family and Drs A Torrelo (Dermatology Service) and JL E´cija (Nephrology Service) from Nin˜o Jesu´s Hospital (Madrid, Spain) for sharing clinical data and profitable debates on the evolution of the patient. This work was funded by the Instituto de Salud Carlos III (ISCIII) grant PS09/00122 and Ministerio de Economı´a y Competitividad SAF201238636.
Alberto Lo´pez-Lera1,2, Juan M. Torres-Canizales1, Sofı´a Garrido1,2, Adelaida Morales3 and Margarita Lo´pez-Trascasa1,2 1
Immunology Unit and Institute for Health Research (IdiPAZ) at La Paz University Hospital, Madrid, Spain; 2Centre for Biomedical Network Research on Rare Diseases (CIBERER), Madrid, Spain and 3Nephrology Unit from Hospital Dr Molina Orosa. Ctra. ArrecifeTinajo, Lanzarote, Spain. E-mail: [email protected] or [email protected] This work was performed at the Immunology Unit of Hospital La Paz, in Madrid (Spain).
REFERENCES Botto M, Dell’Agnola C, Bygrave AE et al. (1998) Homozygous C1q deficiency causes glomerulonephritis associated with multiple apoptotic bodies. Nat Genet 19:56–9 Gaboriaud C, Juanhuix J, Gruez A et al. (2003) The crystal structure of the globular head of complement protein C1q provides a basis for its versatile recognition properties. J Biol Chem 278:46974–82 Kwan KY, Wang JC (2001) Mice lacking DNA topoisomerase IIIbeta develop to maturity but show a reduced mean lifespan. Proc Natl Acad Sci USA 98:5717–21
www.jidonline.org 1153
B Wang Association of HLA-B*1301 and DIHR
Larizza L, Roversi G, Volpi L (2010) RothmundThomson syndrome. Orphanet J Rare Dis 5:2, Review Leyva-Cobia´n F, Moneo I, Mampaso F et al. (1981) Familial C1q deficiency associated with renal and cutaneous disease. Clin Exp Immunol 44:173–80
Roumenina LT, Se`ne D, Radanova M et al. (2011) Functional complement C1q abnormality leads to impaired immune complexes and apoptotic cell clearance. J Immunol 187: 4369–73 Schejbel L, Skattum L, Hagelberg S et al. (2011) Molecular basis of hereditary C1q deficiency—
revisited: identification of several novel disease-causing mutations. Genes Immun 12: 626–34 Sherwood MC, Pincott JR, Goodwin FJ et al. (1987) Dominantly inherited glomerulonephritis and an unusual skin disease. Arch Dis Child 62:1278–80
Different Roads, Same Destination Journal of Investigative Dermatology (2014) 134, 1154–1155; doi:10.1038/jid.2014.9; published online 23 January 2014
TO THE EDITOR I was glad to read the recent online publication of the NEJM article by Zhang et al. (2013) from the Institute of Dermatology, Shangdong Provincial Academy of Medical Sciences, China. From this paper, we noted that our findings published in the Journal of Investigative Dermatology were proved further (Wang et al., 2013). It is interesting to note that we independently applied different research approaches for the same scientific problem and achieved similar conclusions. Six years ago, when I was appointed the Director of the National Center for Leprosy Control and Prevention of China CDC, I had the opportunity to go to leprosaria in China and found several cases of dapsone-induced hypersensitivity reaction (DIHR), a special type of severe drug eruption. From 2009 to 2010, Dr Jianping Shen, a clinical expert of leprosy in our center, performed an epidemiological survey of the mortality factors of leprosy patients in China and found that DIHR ranked as the second highest cause of death (Shen et al., 2011; Tian et al., 2012). I asked Dr Hongsheng Wang, a professor of dermatology and the head of the leprosy laboratory of our center, to select a few DIHR cases for a pilot study of HLA typing in early 2011. A few weeks later, he told me that all the four cases that he had examined were HLA-B*1301 positive. Therefore, we decided to collect all cases of druginduced hypersensitivity syndrome (DIHS) reported to our center through
LepMis (http://218.2.99.162/) and completed this case-control study. In all, we examined 21 cases of DIHR in leprosy patients (see Supplementary Table S1 online) and performed MHC I region typing and genetic polymorphisms of related metabolism enzymes, and we discovered that genetic susceptibility to DIHR is carried on the HLA-B*1301 haplotype, without influence from the genotypes or phenotypes of the important dapsone metabolism enzymes NAT2 and CYP 2C9 (Wang et al., 2013). We performed this study on the basis of the following considerations: first, DIHR is categorized under the DIHS or the drug rash with eosinophilia and systemic symptoms syndromes (Kardaun et al., 2007; Kumari et al., 2011); second, numerous reports have described the associations between human leukocyte antigens (HLAs, especially MHC I) and drug eruptions in patients with various diseases, and that these HLA profiles are useful tools in diagnosing and, moreover, in preventing life-threatening adverse drug reactions (Chung et al., 2004; Mallal et al., 2008; Pavlos et al., 2012); and third, previous studies have proved that genetic polymorphism of human drug metabolism enzymes is a predisposing factor for allergic diseases, lupus erythematosus, Stevens–Johnson syndrome, and toxic epidermal necrolysis (Zielinska et al., 1997; GawronskaSzklarz et al., 1999; Von Schmiedeberg et al., 1999; Wolkenstein et al., 2005). Zhang’s team performed a genomewide association study on 77 DIHR patients and on 2,064 controls and
Accepted article preview online 3 January 2014; published online 23 January 2014
1154 Journal of Investigative Dermatology (2014), Volume 134
discovered that the presence of HLA-B*1301 could predict the risk of DIHR with a sensitivity and specificity of above 85% (Zhang et al., 2013). Those individuals who carry a single copy of HLA-B*1301 run a 34-fold higher risk of being hit by DIHR as compared with those who do not carry this allele, and the risk is magnified 100fold for those who carry two copies of HLA-B*1301. I declare on behalf of the authorship group that we were not aware whether an overlap of study populations existed at the time of submission or publication of our paper, even though Dr Shen had shared patient information with Dr Zhang Furen. After our communication following the recent publication of our letter, Dr Zhang informed me that our four cases of DIHR (cases 7, 10, 12, and 15, Supplementary Table S1) overlapped with his. All four cases were revealed to be HLA-B*1301 positive by our two teams. I am delighted that two different teams in China have found independently the association between HLA-B*1301 and DIHR among leprosy patients in China. I believe that our two teams in China will collaborate in verifying the value of HLA-B*1301 as a predictive biomarker for DIHR in a large-scale prospective study. CONFLICT OF INTEREST The author states no conflict of interest.
Baoxi Wang1 1
Institute of Dermatology, Chinese Academy of Medical Sciences, National Centor of STD and Leprosy Control, China CDC, Nanjing, China E-mail: [email protected]
Connecticut, USA; 7Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut, USA; 8Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA and 9Pediatric Dermatology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA E-mail: [email protected] Work was done in New Haven, Connecticut, USA. SUPPLEMENTARY MATERIAL Supplementary material is linked to the online version of the paper at http://www.nature.com/jid
REFERENCES Fasano O, Aldrich T, Tamanoi F et al. (1984) Analysis of the transforming potential of the human H-ras gene by random mutagenesis. Proc Natl Acad Sci USA 81: 4008–12 Gripp KW, Lin AE (2012) Costello syndrome: a Ras/mitogen activated protein kinase pathway syndrome (rasopathy) resulting from
HRAS germline mutations. Genet Med 14: 285–92
Malumbres M, Barbacid M (2003) RAS oncogenes: the first 30 years. Nat Rev Cancer 3:459–65
Groesser L, Herschberger E, Ruetten A et al. (2012) Postzygotic HRAS and KRAS mutations cause nevus sebaceous and Schimmelpenning syndrome. Nat Genet 44:783–7
Moss C, Larkins S, Stacey M et al. (1993) Epidermal mosaicism and Blaschko’s lines. J Med Genet 30:752–5
Hafner C, Toll A, Gantner S et al. (2012) Keratinocytic epidermal nevi are associated with mosaic RAS mutations. J Med Genet 49:249–53
Peteiro C, Oliva NP, Zulaica A et al. (1989) Woolly-hair nevus: report of a case associated with a verrucous epidermal nevus in the same area. Pediatr Dermatol 6:188–90
Hafner C, Toll A, Real FX (2011) HRAS mutation mosaicism causing urothelial cancer and epidermal nevus. N Engl J Med 365: 1940–2
Shirley MD, Tang H, Gallione CJ et al. (2013) Sturge-Weber syndrome and port-wine stains caused by somatic mutation in GNAQ. N Engl J Med 368:1971–9
Harel S, Christiano AM (2012) Genetics of structural hair disorders. J Invest Dermatol 132:E22–6
Siegel DH, Mann JA, Krol AL et al. (2012) Dermatological phenotype in Costello syndrome: consequences of Ras dysregulation in development. Br J Dermatol 166:601–7
Levinsohn JL, Tian LC, Boyden LM et al. (2013) Whole-exome sequencing reveals somatic mutations in HRAS and KRAS, which cause nevus sebaceus. J Invest Dermatol 133: 827–30 Lindhurst MJ, Sapp JC, Teer JK et al. (2011) A mosaic activating mutation in AKT1 associated with the Proteus syndrome. N Engl J Med 365:611–9
Sun BK, Saggini A, Sarin KY et al. (2013) Mosaic activating RAS mutations in nevus sebaceus and nevus sebaceus syndrome. J Invest Dermatol 133:824–7 Venugopal V, Karthikeyan S, Gnanaraj P et al. (2012) Woolly hair nevus: a rare entity. Int J Trichology 4:42–3
Rothmund–Thomson Syndrome and Glomerulonephritis in a Homozygous C1q-Deficient Patient Due to a Gly164Ser C1qC Mutation Journal of Investigative Dermatology (2014) 134, 1152–1154; doi:10.1038/jid.2013.444; published online 21 November 2013
TO THE EDITOR Rothmund–Thomson syndrome (RTS; MIM#268400) is an autosomal recessive genodermatosis presenting in infancy with poikiloderma and heterogeneous clinical features including short stature, sparse scalp hair, sparse or absent eyelashes and/or eyebrows, juvenile cataracts, skeletal abnormalities, radial ray defects, premature aging, and a predisposition to osteosarcoma (Larizza et al., 2010). Approximately 60–65% of RTS patients carry deleterious mutations in the helicase gene RECQL4 (RTS-type II), predominantly exhibiting poikiloderma, congenital bone defects, and an increased risk of osteosarcoma. The remaining cases, characterized by poikiloderma, ectodermal dysplasia, and juvenile cataracts are negative for the
RECQL4-mutation scan (RTS-type I). At the present time, the cause of RTS-type I is unknown. C1q is the central pattern-recognition molecule in the classical pathway of the complement system. Mutations causing quantitative or functional deficiency of C1q (MIM#613652) have been associated with susceptibility to severe infections, autoimmune disease frequently including systemic lupus erythematosus or overlapping clinical entities, and glomerulonephritis (Botto et al., 1998; Roumenina et al., 2011; Schejbel et al., 2011). Here we report novel and follow-up data on the case of a 40-year-old man belonging to an already published Spanish family (Leyva-Cobia´n et al., 1981) in which three siblings were homozygous
Abbreviations: RECQL4, RecQ protein-like 4; RTS, Rothmund–Thomson syndrome Accepted article preview online 24 October 2013; published online 21 November 2013
1152 Journal of Investigative Dermatology (2014), Volume 134
C1q deficient and presented with renal abnormalities and diffuse glomerular deposits of IgM and C3 compatible with mesangial proliferative glomerulonephritis. Before the age of 12 years, the two boys and a girl also developed oculocutaneus manifestations, poikiloderma, and bilateral cataracts, characteristics compatible with RTS. Both parents and three additional siblings exhibited partial C1q deficiency and remained healthy with no sign of RTS affectation. Studies have been conducted in the only survivor from the pedigree originally published by Leyva-Cobia´n et al. (1981) that provide new data on this unusual case. Clinical features in the patient at diagnosis included macular erythema, erosive skin lesions on the face and finger tips, and bilateral capsular posterior cataracts. At present, he has not developed osteosarcoma or other malignancies.
A Lo´pez-Lera et al. Rothmund–Thomson Syndrome and Glomerulonephritis
Anti-C1QA mAbs Anti-C1QC mAbs Anti-C1Q pAbs A-B (55 kDa) 490 P163
G164
495 L165
C-C (41 kDa)
Mild reduction
A (32 kDa)
Wild type
C (27 kDa) c.490G>A
P163
490 S164 C1q-deficient
495 L165
Full reduction
Single chains C1Q NHP P
C1Q NHP P
C1Q NHP
P
Figure 1. Biochemical and molecular studies in a C1q-deficient individual affected by Rothmund– Thomson syndrome (RTS). (a) Chromatogram showing the homozygous c.490G4A missense mutation in the C1qC gene’s exon 3 of the propositus. (b) C1q was analyzed by western blotting of either normal human plasma (NHP), fresh plasma from the C1q-deficient propositus (P), and purified C1q (C1q) with anti-C1qA mAbs (left column), anti-C1qC mAbs (central column), and anti-C1q pAbs (right column). Each blot was replicated under mild reducing and nonreducing conditions, allowing the detection of the full molecule, A-B and C-C dimers, or A and C single chains. The specific band in the reduced anti-C1qC blot is indicated by a black arrow.
To further characterize his complex phenotype, we carried out PCR amplification and direct sequencing of the C1q-A, -B, -C, and RECQL4 genes, together with a new measurement of the C1q circulating levels, which assessed total absence of the protein in plasma. Examination of the full coding and flanking intronic sequences of the C1q gene cluster on chromosome 1 revealed the homozygous, unreported c.490G4A (Gly164Ser) mutation in the third exon of the C1QC gene (Figure 1a). The glycine residue affected by this previously unreported mutation is adjacent to one of the six hydrophobic patches that define the interfaces among the A-, B-, and C-chains within the globular head (Gaboriaud et al., 2003). Therefore, the substitution of a nonpolar glycine by a bigger and more polar serine residue in such position probably has profound structural implications abolishing either multimerization or secretion of the molecule. Both parents and the remaining siblings were all heterozygous for the mutation. Western blotting of the patient’s circulating C1q with either polyclonal anti-C1q antibodies (C1q pAbs) or mAbs directed against the C1q-A (C1q-A mAbs) and -C (C1q-C mAbs) chains confirmed total absence of the full C1q molecule and also of circulating complexes between A-B and C-C chains in the plasma of the propositus (Figure 1b). No mutation was found in the 21 exons and exon–intron boundaries of the RECQL4 gene on chromosome 8,
thus defining the patient as RTS-type I, which is in good agreement with his pathological condition, predominantly characterized by oculocutaneous affectation. DISCUSSION The co-occurrence of glomerular disease and genodermatosis inherited in an apparent dominant manner is rare but not unique. The phenotypic abnormalities seen in the family presented here resemble some characteristics already reported by Sherwood et al. (1987) in a father-and-son cohort affected by glomerulonephritis and an unusual skin disease resembling RTS. In that case, however, the activity of the classical complement pathway as measured by CH50 hemolytic assay and serum levels of C3 and C4 were all normal, discarding a homozygous defect of C1q. Studies conducted in animal models have also shown that mice lacking DNA topoisomerase III beta, an enzyme interacting with helicases of the RecQ family such as BLM (causative gene of human Bloom progeroid syndrome), develop a complex phenotype, which includes hypertrophy of the spleen and submandibular lymph nodes, glomerulonephritis, and perivascular infiltrates in various organs (Kwan and Wang, 2001). Such a complex phenotype underscores the pleiotropic effects associated with the deregulation of DNA topological maintenance pathways and opens the possibility that genes involved in such pathways could have a role in the development of RTS-type I.
With the present data, the strict coinheritance of the C1q deficiency and RTS traits observed in this cohort suggests the presence of one or several dominant sequence variations in linkage disequilibrium with the C1q locus as a cause for the RTS-type I phenotype in the family. Alternatively, homozygous C1q deficiency could act as a diseasemodifying factor for RTS in the presence of an additional, undescribed mutation in an autosomal chromosome. Written, informed consent from the patients and approval from the research ethics committee of Hospital Universitario La Paz were obtained in order to carry out these studies. CONFLICT OF INTEREST The authors state no conflict of interest.
ACKNOWLEDGMENTS We are indebted to Dr F Leyva-Cobia´n (Valdecilla Hospital, Santander, Spain) for his helpful discussion on the patient and his family and Drs A Torrelo (Dermatology Service) and JL E´cija (Nephrology Service) from Nin˜o Jesu´s Hospital (Madrid, Spain) for sharing clinical data and profitable debates on the evolution of the patient. This work was funded by the Instituto de Salud Carlos III (ISCIII) grant PS09/00122 and Ministerio de Economı´a y Competitividad SAF201238636.
Alberto Lo´pez-Lera1,2, Juan M. Torres-Canizales1, Sofı´a Garrido1,2, Adelaida Morales3 and Margarita Lo´pez-Trascasa1,2 1
Immunology Unit and Institute for Health Research (IdiPAZ) at La Paz University Hospital, Madrid, Spain; 2Centre for Biomedical Network Research on Rare Diseases (CIBERER), Madrid, Spain and 3Nephrology Unit from Hospital Dr Molina Orosa. Ctra. ArrecifeTinajo, Lanzarote, Spain. E-mail: [email protected] or [email protected] This work was performed at the Immunology Unit of Hospital La Paz, in Madrid (Spain).
REFERENCES Botto M, Dell’Agnola C, Bygrave AE et al. (1998) Homozygous C1q deficiency causes glomerulonephritis associated with multiple apoptotic bodies. Nat Genet 19:56–9 Gaboriaud C, Juanhuix J, Gruez A et al. (2003) The crystal structure of the globular head of complement protein C1q provides a basis for its versatile recognition properties. J Biol Chem 278:46974–82 Kwan KY, Wang JC (2001) Mice lacking DNA topoisomerase IIIbeta develop to maturity but show a reduced mean lifespan. Proc Natl Acad Sci USA 98:5717–21
www.jidonline.org 1153
B Wang Association of HLA-B*1301 and DIHR
Larizza L, Roversi G, Volpi L (2010) RothmundThomson syndrome. Orphanet J Rare Dis 5:2, Review Leyva-Cobia´n F, Moneo I, Mampaso F et al. (1981) Familial C1q deficiency associated with renal and cutaneous disease. Clin Exp Immunol 44:173–80
Roumenina LT, Se`ne D, Radanova M et al. (2011) Functional complement C1q abnormality leads to impaired immune complexes and apoptotic cell clearance. J Immunol 187: 4369–73 Schejbel L, Skattum L, Hagelberg S et al. (2011) Molecular basis of hereditary C1q deficiency—
revisited: identification of several novel disease-causing mutations. Genes Immun 12: 626–34 Sherwood MC, Pincott JR, Goodwin FJ et al. (1987) Dominantly inherited glomerulonephritis and an unusual skin disease. Arch Dis Child 62:1278–80
Different Roads, Same Destination Journal of Investigative Dermatology (2014) 134, 1154–1155; doi:10.1038/jid.2014.9; published online 23 January 2014
TO THE EDITOR I was glad to read the recent online publication of the NEJM article by Zhang et al. (2013) from the Institute of Dermatology, Shangdong Provincial Academy of Medical Sciences, China. From this paper, we noted that our findings published in the Journal of Investigative Dermatology were proved further (Wang et al., 2013). It is interesting to note that we independently applied different research approaches for the same scientific problem and achieved similar conclusions. Six years ago, when I was appointed the Director of the National Center for Leprosy Control and Prevention of China CDC, I had the opportunity to go to leprosaria in China and found several cases of dapsone-induced hypersensitivity reaction (DIHR), a special type of severe drug eruption. From 2009 to 2010, Dr Jianping Shen, a clinical expert of leprosy in our center, performed an epidemiological survey of the mortality factors of leprosy patients in China and found that DIHR ranked as the second highest cause of death (Shen et al., 2011; Tian et al., 2012). I asked Dr Hongsheng Wang, a professor of dermatology and the head of the leprosy laboratory of our center, to select a few DIHR cases for a pilot study of HLA typing in early 2011. A few weeks later, he told me that all the four cases that he had examined were HLA-B*1301 positive. Therefore, we decided to collect all cases of druginduced hypersensitivity syndrome (DIHS) reported to our center through
LepMis (http://218.2.99.162/) and completed this case-control study. In all, we examined 21 cases of DIHR in leprosy patients (see Supplementary Table S1 online) and performed MHC I region typing and genetic polymorphisms of related metabolism enzymes, and we discovered that genetic susceptibility to DIHR is carried on the HLA-B*1301 haplotype, without influence from the genotypes or phenotypes of the important dapsone metabolism enzymes NAT2 and CYP 2C9 (Wang et al., 2013). We performed this study on the basis of the following considerations: first, DIHR is categorized under the DIHS or the drug rash with eosinophilia and systemic symptoms syndromes (Kardaun et al., 2007; Kumari et al., 2011); second, numerous reports have described the associations between human leukocyte antigens (HLAs, especially MHC I) and drug eruptions in patients with various diseases, and that these HLA profiles are useful tools in diagnosing and, moreover, in preventing life-threatening adverse drug reactions (Chung et al., 2004; Mallal et al., 2008; Pavlos et al., 2012); and third, previous studies have proved that genetic polymorphism of human drug metabolism enzymes is a predisposing factor for allergic diseases, lupus erythematosus, Stevens–Johnson syndrome, and toxic epidermal necrolysis (Zielinska et al., 1997; GawronskaSzklarz et al., 1999; Von Schmiedeberg et al., 1999; Wolkenstein et al., 2005). Zhang’s team performed a genomewide association study on 77 DIHR patients and on 2,064 controls and
Accepted article preview online 3 January 2014; published online 23 January 2014
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discovered that the presence of HLA-B*1301 could predict the risk of DIHR with a sensitivity and specificity of above 85% (Zhang et al., 2013). Those individuals who carry a single copy of HLA-B*1301 run a 34-fold higher risk of being hit by DIHR as compared with those who do not carry this allele, and the risk is magnified 100fold for those who carry two copies of HLA-B*1301. I declare on behalf of the authorship group that we were not aware whether an overlap of study populations existed at the time of submission or publication of our paper, even though Dr Shen had shared patient information with Dr Zhang Furen. After our communication following the recent publication of our letter, Dr Zhang informed me that our four cases of DIHR (cases 7, 10, 12, and 15, Supplementary Table S1) overlapped with his. All four cases were revealed to be HLA-B*1301 positive by our two teams. I am delighted that two different teams in China have found independently the association between HLA-B*1301 and DIHR among leprosy patients in China. I believe that our two teams in China will collaborate in verifying the value of HLA-B*1301 as a predictive biomarker for DIHR in a large-scale prospective study. CONFLICT OF INTEREST The author states no conflict of interest.
Baoxi Wang1 1
Institute of Dermatology, Chinese Academy of Medical Sciences, National Centor of STD and Leprosy Control, China CDC, Nanjing, China E-mail: [email protected]