Human Molecular Genetics, 2001, Vol. 10, No. 8 875-880
© 2001 Oxford University Press
Mutations in the gene encoding SLURP-1 in Mal de Meleda
1Centre National de Génotypage, 91057 Evry, France, 2Department of Dermatology CHU of Bab-El-Oued, Algiers, Algeria, 3Genoscope, CNS, 91057 Evry, France, 4Dermatogenetic Unit and Laboratory for Cutaneous Biology, Department of Dermatology, CHUV-DHURDV, 1011 Lausanne, Switzerland, 5Department of Dermatology, Dubrovnik General Hospital, Dubrovnik, Croatia, 6Department of Dermatology, Mustapha Hospital, Algiers, Algeria and 7Généthon, 91002 Evry, France
Received 21 December 2000; Revised and Accepted 12 February 2001.
 |
ABSTRACT |
|---|
 TOP ABSTRACT INTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
|---|
Mal de Meleda (MDM) is a rare autosomal recessive skin disorder, characterized by transgressive palmoplantar keratoderma (PPK), keratotic skin lesions, perioral erythema, brachydactyly and nail abnormalities. We report the refinement of our previously described interval of MDM on chromosome 8qter, and the identification of mutations in affected individuals in the ARS (component B) gene, encoding a protein named SLURP-1, for secreted Ly-6/uPAR related protein 1. This protein is a member of the Ly-6/uPAR superfamily, in which most members have been localized in a cluster on chromosome 8q24.3. The amino acid composition of SLURP-1 is homologous to that of toxins such as frog cytotoxin and snake venom neurotoxins and cardiotoxins. Three different homozygous mutations (a deletion, a nonsense and a splice site mutation) were detected in 19 families of Algerian and Croatian origin, suggesting founder effects. Moreover, one of the common haplotypes presenting the same mutation was shared by families from both populations. Secreted and receptor proteins of the Ly-6/uPAR superfamily have been implicated in transmembrane signal transduction, cell activation and cell adhesion. This is the first instance of a secreted protein being involved in a PPK.
|
INTRODUCTION |
|---|
|
TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
|---|
The hereditary palmoplantar keratodermas (PPKs) are a hetero-geneous group of skin diseases characterized by hyperkeratosis on the palms and soles with or without associated ectodermal or non-ectodermal features (1). In addition to defects in various structural proteins such as keratin intermediate filaments and loricrin, the major precursor protein of the cornified cell envelope, mutations of molecules involved in filament anchorage (plakoglobin, desmoplakin), cellular adhesion (desmoglein 1, plakophillin), formation of gap-junctions (connexins 26, 30 and 31) or proteolysis (cathepsin C) cause diverse variants of PPKs (1–3).
Mal de Meleda (MDM, MIM 248300) is a rare autosomal recessive PPK, characterized by keratotic skin lesions, particularly over the joints, perioral erythema, brachydactyly and nail abnormalities. Associated hyperhidrosis and superinfection frequently cause malodorous maceration. The progressive lesions can lead to severe functional handicap with reduced mobility of hands and feet including spontaneous amputation of digits.
We previously reported the localization of the MDM gene to chromosome 8qter by linkage analysis in two large consanguineous families (families 1 and 2), within an interval of at least 3 cM, but without definition of the telomeric limit (4). We refined this interval using a combination of homozygosity mapping and linkage disequilibrium analysis in 19 families. Mutation analysis of candidate genes in the interval revealed three different homozygous mutations in the ARS (component B) gene, encoding SLURP-1 (secreted Ly-6/uPAR related protein 1) (5) in these families. Secreted and receptor proteins of the Ly-6/uPAR superfamily have been implicated in transmembrane signal transduction (5), cell activation and cell adhesion (6).
|
RESULTS |
|---|
|
TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
|---|
Clinical features and patient origins
We studied 12 kindreds of Algerian origin and 7 kindreds from Croatia, including Meleda island (Mljet, which was formerly a leper colony), with a total of 41 patients and 104 unaffected family members. Three of these families have been previously described (families 1, 2 and 5; Fig. 1). Affected subjects presented typical symptoms of MDM, with the exception of three patients from two Algerian families (kindreds 7 and 10), who presented a phenotype with unusual presence of lesions in the inguinal area of the body and were therefore initially diagnosed as affected by a recessive form of progressive and symmetric erythrokeratodermia (PSEK, MIM 602036). Fourteen families were known to be consanguineous (13 from first cousin marriages and one from an uncle/niece marriage); in five families no consanguinity loop was found.
|
Linkage studies
Genotyping in the 8qter interval was performed using eight markers from public databases and five new markers which we developed (Table 1). All the patients showed a homozygous region for markers at 8qter, even when they were not known to be consanguineous (Fig. 1). The maximum LOD score was 24.19 for the marker CNG003 at
= 0.0. Recombination events and loss of homozygosity reduced the smallest cosegregating interval to 1 cM, containing three microsatellite markers: CNG003, D8S1751 and D8S1836. Flanking markers were CNG002 and CNG004, based on recombination events observed in families 1, 14, 17 and 19 for the centromeric part and in families 1 and 5 for the telomere. Markers mapping within the interval defined by recombination events showed, as expected, strong and significant allelic association with MDM (Pexcess = 0.70, 0.68 and 0.63 at CNG003, D8S1751 and D8S1836, respectively; 
2 < 0.0001) (Fig. 1). Three ancestral haplotypes were observed; the first (3-3-2) was found in nine large Algerian and four Croatian kindreds. A second haplotype (7-1-5) was observed in three Algerian families and, finally, a third haplotype (8-1-4) was present in three Croatian families (Fig. 1).
|
Physical map and identification of candidate genes
We constructed a partial physical map consisting of five neighboring contigs: centromere- 18393, 19078, 15579 (partly) // 16892 // 16007 -telomere, which was in agreement with recent data from ‘Golden Path’ (http://genome.ucsc.edu/). Two markers (CNG003 and D8S1751) showing significant linkage disequilibrium were contained in contig 16892, whereas the third marker (D8S1836) was not found in any of the identified contigs. The contig 16892 includes six overlapping sequences, spanning about 300 kb: AC073385, AB000381, AC011976, AC015718, AF176678 and AF235094. They were compared with the annotated sequences of databases such as Ensembl for their gene content. Contig 16892 contains a cluster of Ly-6 homologous human genes, including E48 (Ly-6D-pending) (7), GML (8) or glycosylphosphatidylinositol (GPI)-anchored molecule-like protein (Ly-6DL, MIM 602370), ARS (5) and prostate stem cell antigen (PSCA) (9). All of them are members of the Ly-6/uPAR family of receptor and secreted proteins. The Ly-6 proteins were initially identified as mouse lymphocyte antigens; uPAR is the urokinase-type plasminogen activator receptor. This family is defined by a highly conserved pattern of disulfide bridges (10,11) and a gene structure which usually contains four exons, the first of which is untranslated.
Mutation analysis
The E48 gene is known to be expressed in human keratinocytes, but not in lymphocytes (12) and has been demonstrated to be involved in the desmosomal cell–cell adhesion of keratinocytes (13), making it a candidate gene for PPK. E48 was shown to contain only three exons (12). Immunofluorescence analysis in patient skin with an antibody directed against E48 demonstrated a normal expression pattern (data not shown), suggesting that this gene is not the MDM gene. This finding was further supported by sequence analysis showing no mutations in the three coding exons of the E48 gene. Sequencing of the three coding exons of the GML gene, which is induced by the p53 tumor suppressor and shares a similar genomic organization with the other genes of the Ly-6 family (8), also failed to reveal mutations. The ARS (component B) gene is also predicted to contain three exons, and to encode a protein of 103 amino acids, but since the genomic sequence is only available in GenBank, the existence of a first untranslated exon cannot be completely excluded. Mutation analysis of the three exons of the ARS (component B) gene in our 19 families revealed three different homozygous mutations corresponding to the three different ancestral haplotypes. The first haplotype was observed in patients from 13 families of Algerian and/or Croatian origin (Fig. 1), in which we found a single nucleotide deletion (82delT) leading to a frameshift (Fig. 2) and creation of a premature stop codon at amino acid position 32. A splice site mutation affecting the invariant G of the donor splice site GT dinucleotide in the second intron was found in three Algerian families, which exhibit the second haplotype. This mutation is expected to lead to aberrant splicing. Three Croatian families showed a point mutation at position 286 (C286T), which changes arginine at position 96 to a stop codon, and which corresponds to the third haplotype (Fig. 2). Although this mutation is at the end of the protein, the truncated version of the protein lacks a cysteine implicated in one of the highly conserved disulfide bridges.
|
Expression analysis
Expression of SLURP-1 transcripts was investigated in cultured keratinocytes and tissue samples from normal and affected individuals. Northern blot analysis (Fig. 3A) showed strong expression of SLURP-1 mRNA in cultured keratinocytes derived from a plantar skin biopsy from a normal control subject, but absence of expression in keratinocytes from the involved plantar skin of patients. It was not detected in cultured keratinocytes from normal trunk skin or in biopsies from control trunk epidermis. On the other hand, RT–PCR analysis, which is more sensitive (Fig. 3B), revealed SLURP-1 mRNA in cultured keratinocytes from skin biopsies from different body sites in both controls and MDM patients. In biopsies from normal subjects, SLURP-1 mRNA was found to be expressed in epidermis, foreskin, scalp skin and fetal bladder, but not in the other tissues tested (Fig. 3B). Interestingly, in a patient with a splice site mutation we found two RT–PCR products with different sizes compared with controls, indicating that no normal mRNA is formed in this patient. These results indicate that SLURP-1 is mainly expressed in plantar, and most likely, in palmar skin, which corresponds to the sites of MDM lesions.
|
|
DISCUSSION |
|---|
|
TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
|---|
This is the first time that a secreted protein has been implicated in a PPK. The Ly-6/uPAR superfamily of proteins was initially identified in mice. The Ly-6 locus encodes at least seven structurally related proteins clustered on murine chromosome 15. On the basis of synteny, it has been suggested that the human homologs reside on human chromosome 8q, distal to Myc-1, with the exception of protectin (CD59) which is located on 11p13 (14). Attempts to isolate the human homologs through interspecies homology have been hampered by an apparently rapid divergence of genes between species. The superfamily has been classified into two subfamilies (5), the first of which includes GPI-anchored receptor proteins with 10 conserved cysteine residues such as retinoic acid-induced gene E (RIG-E) (15), the E48 antigen (7), the PSCA (9), CD59 or protectin (14) and uPAR. The ligands for the Ly-6-related human CD59 and uPAR are known and contain EGF-like repeats (6). Similarly, the first ligand described for a mouse Ly-6 protein (Ly-6D or ThB, the murine homolog for E48) was recently identified as a small 9 kDa protein with significant homology to the EGF-repeats of the Notch family (16). The second subfamily, characterized by lack of a GPI-anchoring signal sequence and at least eight of the 10 conserved cysteines, includes secreted snake and frog cytotoxins and the recently described SLURP-1 protein, which is the first secreted mammalian member of the Ly-6/uPAR superfamily to be reported. SLURP-1 was isolated from peptide libraries prepared from an ultrafiltrate of human blood and from urine (5). Its function is unknown at present but phylogenetic analysis has shown that it is more closely related to the snake cytotoxins than to the mammalian GPI-anchored receptors (5). Therefore, SLURP-1 is likely to function as a ligand for a receptor yet to be identified. As a secreted molecule it may compete with members of the GPI-anchored receptor Ly-6 subfamily for binding to ligands (e.g. urokinase-type plasminogen activator) or to other molecules containing EGF-repeats including Notch, which are similar to the processed Notch-ligand delta (17). Finally, SLURP-1 may interfere with weak intercellular adhesion, as has been shown for Ly-6D and Ly-6DL (16). The discovery of SLURP-1 as the cause of a PPK of the Meleda type implicates yet another type of protein in the development of PPKs.
|
MATERIALS AND METHODS |
|---|
|
TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
|---|
Human material
Three dermatologists (B.B., D.H. and A.B.-K.) recorded clinical data, pedigree information and performed skin biopsies for histological examination (18). Blood samples were collected from each participant family member and skin biopsies were obtained from most of the patients after obtaining written informed consent. DNA extraction from peripheral blood leukocytes was performed using standard procedures.
Genetic analysis
Genotyping with fluorescent markers was carried out as described previously (4). Haplotypes were constructed assuming the most parsimonious linkage phase. Linkage programs were used on the assumption of autosomal recessive inheritance, full penetrance and a disease frequency of 1 in 100 000 in the general population. Pairwise LOD scores were calculated with the MLINK program of the LINKAGE 5.1 package (19), incorporating consanguineous loops into the pedigree files if the information about consanguinity was given by the patients. For linkage disequilibrium analysis, we examined the frequencies of each allele in the affected and the normal chromosome population to define the presumed ancestral haplotype. Chromosomes shared by two siblings or homozygous were counted only once. The excess of the disease-associated alleles was calculated using the Pexcess equation (20): Pexcess = (Paffected – pnormal) / (1 – Pnormal), in which Paffected and Pnormal denote the frequency of the disease-associated allele on disease-bearing (34 chromosomes) and normal chromosomes (40 chromosomes), respectively. For 2 estimation, we used the combined-allele method (21). The significance level (
= 0.05) was corrected using Bonferroni’s procedure (22) as follows: ' = 1 – (1 – )1/L, where L is the number of individual tests (13 tests in our study) and was 0.003.
Construction of a physical contig map
The sequences from the interval between the marker D8S1717 and the telomere were identified by the Genoscope working draft utility (http://www.genoscope.cns.fr/cgi-bin/WD.cgi). Based on the Human Gene Map (http://www.ncbi.nlm.nih.gov.genemap), this tool identified working draft sequences which contained one or more RHdb markers from the interval by e-PCR. These genomic sequences include cosmids, P1-derived artificial chromosome (PAC) and bacterial artificial chromosome (BAC) clones, most of which were unfinished sequences (phase 0–1). To construct a physical contig map of the region, we performed a search for BAC end sequences in the TIGR database with these working draft sequences. We identified additional BAC clones, which we analyzed on the human fingerprint contig map of the Washington University Genome Center, which permitted assembly of clones and contigs in a physical order. A strategy of extension and junction formation between contigs was followed, using the Sequence Tag Connectors approach. The resulting partial physical map of our interval consisted of five clone contigs containing about three quarters of the RHdb markers from the gene map interval. The two flanking contigs could be excluded due to their content of markers which showed recombination events in affected individuals. Ten new (CA)n repeat microsatellites from sequences of the three remaining contigs were developed (Table 1), but only five of them were polymorphic and useful for linkage analysis. Sequences from the three contigs were compared with databases such as the Ensembl genome server (http://www.ensembl.org), where results of new and already known gene structures were annotated by several gene prediction programs, in order to identify candidate genes for mutation analysis.
Mutation screening
Mutation analysis was performed in affected patients and in both parents in the 19 families, and in supplementary non-affected siblings in cases of missing parents. We designed intronic oligonucleotide primers for ARS, E48 and GML flanking the coding exons (Table 2) using the Primer3 program from the genomic sequences X99977, X82693 and AB000381, respectively. The PCR reaction was performed in a 50 µl volume containing 100 ng of genomic DNA (in 10 µl) using standard procedures (23). After an initial denaturation step at 96°C for 5 min, Taq polymerase was added at 94°C (hot start) and 35 cycles of amplification were performed consisting of 30 s at 94°C, 40 s at the optimal annealing temperature (58°C) followed by a 10 min terminal elongation step. Purified PCR products (1–1.5 µl) were added to 1 µl of sense or antisense primer (10 µM) and 3 µl of BigDye terminator mix (PE Applied Biosystems). The linear amplification consisted of an initial denaturation step at 96°C, 25 cycles of 10 s of denaturation at 96°C, a 5 s annealing step (55–61°C) and a 4 min extension step at 60°C. The reaction products were purified and sequenced on an Applied Biosystem Sequencer 3700. Both strands from all patients and controls were sequenced for the entire coding region and the intron/exon boundaries.
|
Immunofluorescence analysis
Frozen skin from patients and control individuals was incubated with a monoclonal antibody (mAb E48) (7) directed against E48 at a 1:100 dilution. Antibodies were then visualized by sequential incubation with biotinylated horse anti-mouse IgG (Vector Laboratories) at a dilution of 1:100 and TexasRed Streptavidin (Gibco BRL) at a dilution of 1:400.
RNA isolation, northern blot analysis and RT–PCR
RNA isolation from cultured keratinocytes and skin biopsies was carried out as previously described (24). We generated specific PCR probes for the 3'UTR of ARS (nucleotides 1852–1991 of X99977). After purification using the QIAquick PCR purification kit (Qiagen), these probes were radiolabeled with 32P and exposed to Kodak film for 3 days at –80°C. The SLURP1-specific probes were hybridized to human keratinocyte total RNA (13 µg) from different skin areas (plantar skin of patients, normal controls and trunk epidermis from controls). RT–PCR was performed using the OneStep RT–PCR kit (Qiagen) with the forward primer from exon 1 (nucleotides 572–592) and reverse primers (nucleotides 1817–1797) from exon 3. The RT–PCR conditions were 50°C for 30 min for reverse transcription, incubation at 95°C for 15 min for inactivation of reverse transcriptases, followed by 35 cycles of 94°C for 1 min, 60°C for 30 s and 72°C for 50 s, and final extension for 10 min at 72°C. RT–PCR fragments were run on 1% agarose gel and visualized under an ultraviolet transilluminator.
GenBank and SwissProt accession numbers
ARS (component B) gene, X99977; SLURP-1, P55000; E48, X82693; and GML, AB000381.
|
ACKNOWLEDGEMENTS |
|---|
We wish to thank the family members for their participation and we would like to acknowledge the technical support of the Généthon DNA bank. We are especially grateful to Susan Cure for help in writing this manuscript. This study was supported by the Centre National de Génotypage (CNG), Association Française contre les Myopathies (AFM) and Généthon. D.H. was supported by the Swiss National Foundation.
|
FOOTNOTES |
|---|
+ To whom correspondence should be addressed. Tel.: +33 1 60 87 83 57; Fax: +33 1 60 87 83 83; Email: fischer@cng.fr
|
REFERENCES |
|---|
|
TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
|---|
1 Kelsell, D.P. and Stevens, H.P. (1999) The palmoplantar keratodermas: much more than palms and soles. Mol. Med. Today, 5, 107–113.[Web of Science][Medline]
2 Toomes, C., James, J., Wood, A.J., Wu, C.L., McCormick, D., Lench, N., Hewitt, C., Moynihan, L., Roberts, E., Woods, C.G. et al. (1999) Loss-of-function mutations in the cathepsin C gene result in periodontal disease and palmoplantar keratosis. Nature Genet., 23, 421–424.[Web of Science][Medline]
3 Norgett, E.E., Hatsell, S.J., Carvajal-Huerta, L., Ruiz Cabezas, J.C., Common, J., Purkis, P.E., Whittock, N., Leigh, I.M., Stevens, H.P. and Kelsell, D.P. (2000) Recessive mutation in desmoplakin disrupts desmoplakin-intermediate filament interactions and causes dilated cardiomyopathy, woolly hair and keratoderma. Hum. Mol. Genet., 9, 2761–2766.
4 Fischer, J., Bouadjar, B., Heilig, R., Fizames, C., Prud’homme, J.F. and Weissenbach, J. (1998) Genetic linkage of Meleda disease to chromosome 8qter. Eur. J. Hum. Genet., 6, 542–547.[Web of Science][Medline]
5 Adermann, K., Wattler, F., Wattler S., Heine, G., Meyer, M., Forssmann, W.G. and Nehls, M. (1999) Structural and phylogenetic characterization of human SLURP-1, the first secreted mammalian member of the Ly6/uPAR protein superfamily. Protein Sci., 8, 810–819.[Web of Science][Medline]
6 Gumley, T.P., McKenzie, I.F.C. and Sandrin, M.S. (1995) Tissue expression, structure and function of the murine Ly-6 family of molecules. Immunol. Cell Biol., 73, 277–296.[Medline]
7 Brakenhoff, R.H., Gerretsen, M., Knippels, E.M.C., van Dijk, M., van Essen, H., Weghuis, D.O., Sinke, R.J., Snow, G.B. and van Dongen, G.A.M.S. (1995) The human E48 antigen, highly homologous with the murine Ly-6 antigen ThB, is a GPI-anchored molecule apparently involved in keratinocyte cell-cell adhesion. J. Cell Biol., 129, 1677–1689.
8 Kimura, Y., Furuhata, T., Urano, T., Hirata, K., Nakamura, Y. and Tokino, T. (1997) Genomic structure and chromosomal localization of GML (GPI-anchored molecule-like protein), a gene induced by p53. Genomics, 41, 477–480.[Web of Science][Medline]
9 Reiter, R.E., Gu, Z., Watabe, T., Thomas, G., Szigeti, K., Davis, E., Wahl, M., Nisitani, S., Yamashiro, J., Le Beau, M.M. et al. (1998) Prostate stem cell antigen: a cell surface marker overexpressed in prostate cancer. Proc. Natl Acad. Sci. USA, 95, 1735–1740.
10 Ploug, M., Kjalke, M., Ronne, E., Weidle, U., Hoyer-Hansen, G. and Dano, K. (1993) Localisation of the disulfide bonds in the NH2-terminal domain of the cellular receptor for human urokinase-type plasminogen activator. A domain structure belonging to a novel superfamily of glycolipid-anchored membrane proteins. J. Biol. Chem., 268, 17539–17546.
11 Fletcher, C.M., Harrison, R.A., Lachmann, P.J. and Neuhaus, D. (1993) Sequence-specific 1H-NMR assignments and folding topology of human CD59. Protein Sci., 12, 2015–2027.
12 Brakenhoff, R.H., van Dijk, M., Knippels, E.M.C. and Snow, G.B. (1997) A gain of novel tissue specificity in the human Ly-6 gene E48. J. Immunol., 159, 4879–4886.[Abstract]
13 Schrijvers, A.H.G.J., Gerretsen, M., Fritz, J.M., van Walsum, M., Quak, J.J., Snow, G.B. and van Dongen, G.A. (1991) Evidence for a role of monoclonal antibody E48 defined antigen in cell-cell adhesion in squamous ephithelia and head and neck squamous cell carcinoma. Exp. Cell Res., 196, 264–269.[Web of Science][Medline]
14 Bickmore, W.A., Longbottom, D., Oghene, K., Fletcher, J.M. and van Heyningen, V. (1993) Colocalization of the human CD59 gene to 11p13 with the MIC11 cell surface antigen. Genomics, 17, 129–135.[Web of Science][Medline]
15 Mao, M., Yu, M., Tong, J.H., Ye, J., Zhu, J., Huang, O.H., Fu, G., Yu, L., Zhao, S.Y., Waxman, S. et al. (1996) RIG-E, a human homolog of the murine Ly-6 family, is induced by retinoic acid during the differentiation of acute promyelocytic leukemia cells. Proc. Natl Acad. Sci. USA, 93, 5910–5914.
16 Apostolopoulos, J., McKenzie, I.F.C. and Sandrin, M.S. (2000) Ly6d-L, a cell surface ligand for mouse Ly6d. Immunity, 12, 223–232.[Web of Science][Medline]
17 Qi, H., Rand, M.D., Wu, X., Sestan, N., Wang, W., Rakic, P., Xu, T. and Artavanis-Tsakonas, S. (1999) Processing of the Notch ligand delta by the metalloprotease Kuzbanian. Science, 283, 91–94.
18 Bouadjar, B., Benmazouzia, S., Prud’homme, J.F., Cure, S. and Fischer, J. (2000) Clinical and genetic studies of 3 large, consanguineous, Algerian families with mal de Meleda. Arch. Dermatol., 136, 1247–1252.
19 Lathrop, G.M., Lalouel, J.M., Julier, C. and Ott, J. (1985) Multilocus linkage analysis in humans: detection and estimation of recombination. Am. J. Hum. Genet., 37, 482–498.[Web of Science][Medline]
20 Hästbacka, J., de la Chapelle, A., Mahtani, M.M., Clines, G., Reeve-Daly, M.P., Daly, M., Hamilton, B.A., Kusumi, K., Trivedi, B., Weaver, A. et al. (1994) The diastrophic dysplasia gene encodes a novel sulfate transporter: positional cloning by fine-structure linkage disequilibrium mapping. Cell, 78, 1073–1087.[Web of Science][Medline]
21 Aksentijevich, I., Pras, E., Gruberg, L., Shen, Y., Holman, K., Helling, S., Prosen, L., Sutherland, G.R., Richards, R.I., Dean, M. et al. (1993) Familial Mediterranean fever (FMF) in Moroccan jews: demonstration of a founder effect by extended haplotype analysis. Am. J. Hum. Genet., 53, 644–651.[Web of Science][Medline]
22 Weir, B.S. (1990) Genetic Data Analysis. Sinauer, Sunderland, MA.
23 Vignal, A., Gyapay, G., Hazan, J., Nguyen, S., Dupraz, C., Cheron, N., Becuwe, N., Tranchant, M. and Weissenbach, J. (1993) Nonradioactive multiplex procedure for genotyping of microsatellite markers. In Adolph, K.W. (ed.), Gene and Chromosome Analysis. Part A, Vol. 1. Academic Press, San Diego, pp. 211–221.
24 Huber, M., Yee, V.C., Burri, N., Vikerfors, E., Lavrijsen, A.P., Paller, A.S. and Hohl, D. (1997) Consequences of seven novel mutations on the expression and structure of keratinocyte transglutaminase. J. Biol. Chem., 272, 21018–21026.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  K. Kabashima, J.-i. Sakabe, Y. Yamada, and Y. Tokura "Nagashima-Type" Keratosis as a Novel Entity in the Palmoplantar Keratoderma Category Arch Dermatol, March 1, 2008; 144(3): 375 - 379. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Parmentier, P. M. Steijlen, and M. A. M. van Steensel Recessive Palmoplantar Keratodermas: A Fertile Biological Hunting Ground Arch Dermatol, March 1, 2008; 144(3): 384 - 385. [Full Text] [PDF]
|
|
|
|
 |
|
 N. Radoja, A. Gazel, T. Banno, S. Yano, and M. Blumenberg Transcriptional profiling of epidermal differentiation Physiol Genomics, January 12, 2007; 27(1): 65 - 78. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S.-H. Li, R. K.-K. Lee, M.-H. Lin, Y.-M. Hwu, C.-H. Lu, Y.-J. Chen, H.-C. Chen, W.-H. Chang, and W.-C. Chang SSLP-1, a secreted Ly-6 protein purified from mouse seminal vesicle fluid. Reproduction, September 1, 2006; 132(3): 493 - 500. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Norman, J. Davis, and J. Piatigorsky Postnatal Gene Expression in the Normal Mouse Cornea by SAGE Invest. Ophthalmol. Vis. Sci., February 1, 2004; 45(2): 429 - 440. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A Martinez-Mir, A Zlotogorski, D Londono, D Gordon, A Grunn, E Uribe, L Horev, I M Ruiz, N O Davalos, O Alayan, et al. Identification of a locus for type I punctate palmoplantar keratoderma on chromosome 15q22-q24 J. Med. Genet., December 1, 2003; 40(12): 872 - 878. [Abstract] [Full Text]
|
|
|
|
 |
|
 F. Chimienti, R. C. Hogg, L. Plantard, C. Lehmann, N. Brakch, J. Fischer, M. Huber, D. Bertrand, and D. Hohl Identification of SLURP-1 as an epidermal neuromodulator explains the clinical phenotype of Mal de Meleda Hum. Mol. Genet., November 15, 2003; 12(22): 3017 - 3024. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Jobard, B. Bouadjar, F. Caux, S. Hadj-Rabia, C. Has, F. Matsuda, J. Weissenbach, M. Lathrop, J.-F. Prud'homme, and J. Fischer Identification of mutations in a new gene encoding a FERM family protein with a pleckstrin homology domain in Kindler syndrome Hum. Mol. Genet., April 15, 2003; 12(8): 925 - 935. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Rudan, N. Smolej-Narancic, H. Campbell, A. Carothers, A. Wright, B. Janicijevic, and P. Rudan Inbreeding and the Genetic Complexity of Human Hypertension Genetics, March 1, 2003; 163(3): 1011 - 1021. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. C. Henderson, M. M. Kamdar, and A. Bamezai Ly-6A.2 Expression Regulates Antigen-Specific CD4+ T Cell Proliferation and Cytokine Production J. Immunol., January 1, 2002; 168(1): 118 - 126. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||