Cathepsin C gene 5'-untranslated region mutation in papillon-lefèvre syndrome.

BACKGROUND: Papillon-Lefèvre syndrome (PLS) is a rare autosomal recessive disorder characterized by palmoplantar keratoderma together with a severe form of generalized aggressive periodontitis and associated with mutations in cathepsin C gene (CTSC). OBJECTIVE: To investigate the clinical and mutational characteristics of 6 PLS patients from 4 unrelated Slovenian families. METHODS: CTSC mutational and functional analyses were performed. RESULTS: In all patients, a novel homozygous substitution, c.-55C>A, in the CTSC 5'-untranslated region (UTR) was detected on genomic DNA level and confirmed by mRNA analysis, resulting in the almost complete loss of CTSC mRNA expression and CTSC activity. In silico analysis revealed the potential of the mutation to disrupt putative transcription factor binding sites (TFBSs) for AP-2 and Sp families of transcription factors. CONCLUSION: Identification of a novel CTSC 5'-UTR mutation together with a severe reduction of CTSC mRNA expression and virtually nonexistent CTSC activity was suggestive of a novel mechanism of TFBS dysfunction associated with PLS.

Darier disease in Slovenia: spectrum of ATP2A2 mutations and relation to patients' phenotypes.

ATP2A2 encodes the sarco/endoplasmic reticulum Ca2+- ATPase (SERCA2) and has been identified as a defective gene in Darier disease (DD). It is an autosomal dominant genodermatosis, which is characterized by loss of adhesion between suprabasal epidermal keratinocytes (acantholysis) and abnormal keratinization (dyskeratosis). We examined 28 Slovenian patients with DD (the cohort of patients represents over 50% of all DD patients in Slovenia) and screened genomic DNA for ATP2A2 mutations and RNA for splice site mutations. We identified 7 different ATP2A2 mutations, 4 of which are novel: A516P, R559G, 544+1del6, and 1762-6del18. We also found two previously described polymorphisms 2741+54 G>A in intron XVIII and 2172 G>A (A724A) in exon 15, with allele frequencies of 64.2% and 11.3%, respectively. The mutations are scattered throughout the gene and affect the actuator, phosphorylation, stalk and transmembrane domains of SERCA2. A P160L mutation in a Slovene patient with severe DD and a history of deafness is another consistent genotype-phenotype correlation. It seems that mutations of the ATP2A2 gene may also play a role in the pathogenesis of deafness, which seems to be a new phenotypic characteristic of DD patients.

Four novel ATP2A2 mutations in Slovenian patients with Darier disease.

BACKGROUND: Darier disease (DD) is an autosomal dominant genodermatosis caused by mutations in the ATP2A2 gene. It has been reported that depletion of Ca(2+) stores within the endoplasmic reticulum of keratinocytes is associated with impaired cell cycle regulation and terminal differentiation. Mechanical stress, heat, or UV irradiation might delay cell cycle exit and permit progression into the quiescent stage without repair. When there is associated DNA damage, this can lead to an accumulation of secondary somatic mutations and possible clonal proliferation of damaged keratinocyes within keratotic papules and plaques. OBJECTIVE: We sought to present clinical, demographic, and genetic analysis of the cohort of Slovenian patients with DD, which represents 52% of DD patients in the country. METHODS: We examined 28 Slovenians with DD and screened genomic DNA for ATP2A2 mutations and RNA for splice site mutations. RESULTS: The estimated prevalence of the disease in Slovenia is 2.7/100.000. We identified 7 different ATP2A2 mutations, 4 of which are novel: A516P, R559G, 463-6del6, and 1762-6del18. We also found two previously described polymorphisms in intron XVIII (2741 + 54 G>A) and in exon 15 (2172 G>A; A724A), with allele frequencies of 64.15% and 11.32%, respectively. There was a history of perceptive deafness in two DD patients from two families. LIMITATIONS: Analysis of SERCA2 expression, measurements of Ca(2+) uptake and their influence on desmosomal assembly in vitro would add additional value to the study. Although single-stranded conformational analysis (SSCP) is a common and accepted method for screening for the presence of mutations, it does miss 10% to 20% of mutations. CONCLUSIONS: We identified 4 novel ATP2A2 mutations in Slovenian patients with DD. Deafness seems to be a new phenotypic characteristic of DD patients.

Hereditary palmoplantar keratoderma type papulosa in Slovenia.

BACKGROUND: Hereditary palmoplantar keratodermas (HPPK) are relatively frequent in Slovenia; however, the papulosa type of HPPK is rare. Epidemiological data are scarce; a population study in Croatia revealed a prevalence of 1.17/100,000 inhabitants. According to the preliminary data, it seems that HPPK papulosa is more common in Slovenia than in other countries. Efforts were made to identify all patients with HPPK papulosa in Slovenia. PATIENTS AND METHODS: Existing hospital and outpatient records served as a starting point. Patients and their relatives were invited for examination. When necessary for preparing pedigrees, we visited patients. RESULTS: Altogether 66 patients were observed, giving a prevalence of 3.3/100,000 inhabitants. 62 patients belonged to 11 unrelated families with two or more affected members and there were also four isolated cases. Our investigation points to an autosomal dominant mode of inheritance. All of the routine biochemical and hematologic tests were within normal limits. No malignancies were observed, nor were such data revealed in patients' histories. Thickened nail-plates were observed in three patients. CONCLUSIONS: The prevalence of HPPK papulosa in Slovenia is higher than in other countries studied. Further loci mentioned in literature suggest a genetic heterogeneity in this condition.

Hereditary diffuse palmoplantar keratodermas in Slovenia: epidemiologic foci in remote rural areas.

BACKGROUND: Previous studies carried out in Slovenia revealed a high frequency of cases of hereditary diffuse palmoplantar keratodermas (DPPK). The relatively small total population of about two million in a small territory and an efficient public health service were favorable preconditions for such a study. METHODS: Existing hospital and outpatient department records served as starting points. Patients were invited to come for a follow-up examination, and visiting the patients at their homes enabled us to gather further data. Thus efforts were made to include all patients with hereditary DPPK in Slovenia. RESULTS: Altogether 170 DPPK patients were detected, giving a prevalence of 8.3 per 100,000 inhabitants. The patients originated from remote, mostly mountainous districts, where the local DPPK prevalence highly significantly exceeded the average Slovene prevalence. The segregation ratio showed an autosomal dominant mode of inheritance. The percentage of persons affected was 34.4% (95% confidence interval 29.8-39.4), lower than expected for autosomal dominant inheritance (the difference is highly significant, P < 0.00001; exact binomial test). CONCLUSION: One autosomal dominant gene alone does not fully explain the transmission of the disorder to siblings. Evidence is produced that additional factors are necessary for the transmission of this genetic condition. The degree of consanguinity and the physical pressure on palms and soles seem to play an important part. It is reasonable to expect that molecular-biology studies linked to the epidemiological data could contribute to the solution of the problem.

Clinical and genetic heterogeneity of erythrokeratoderma variabilis.

The skin disease erythrokeratoderma variabilis (EKV) has been shown to be associated with mutations in GJB3 and GJB4 encoding connexin (Cx)31 and Cx30.3, respectively. Gap junctions composed of Cx proteins are intracellular channels providing a mechanism of synchronized cellular response facilitating metabolic and electronic functions of the cell. In the skin, Cx31 and Cx30.3 are expressed in the stratum granulosum of the epidermis with a suggested role in late keratinocyte differentiation. Molecular investigations of GJB3 and GJB4 were performed in five pedigrees and three sporadic cases of EKV. Mutational analyzes revealed disease-associated Cx31 or Cx30.3 mutations in only three probands of which two were novel mutations and one was a recurrent mutation. These genetic studies further demonstrate the heterogeneous nature of the erythrokeratodermas as not all individuals that were clinically diagnosed with EKV harbor Cx31 or Cx30.3 mutations.

Clinical and pathological features of pachyonychia congenita.

Pachyonychia congenita (PC) is a rare genodermatosis affecting the nails, skin, oral mucosae, larynx, hair, and teeth. Pathogenic mutations in keratins K6a or K16 are associated with the PC-1 phenotype whereas K6b and K17 mutations are associated with the PC-2 phenotype. Analysis of clinical, pathological, and genetic data from the literature and two research registries reveal that >97% of PC cases exhibit fingernail and toenail thickening, and painful plantar keratoderma. Prospective evaluation of 57 PC patients from 41 families revealed variable clinical findings: hyperhidrosis (79%), oral leukokeratosis (75%), follicular keratosis (65%), palmar keratoderma (60%), cutaneous cysts (35%), hoarseness or laryngeal involvement (16%), coarse or twisted hair (26%), early primary tooth loss (14%), and presence of natal or prenatal teeth (2%). Stratification of these data by keratin mutation confirmed the increased incidence of cyst formation and natal teeth among PC-2 patients, although cysts were more commonly seen in PC-1 than previously reported (25%-33%). Previously unreported clinical features of PC include development of painful oral and nipple lesions during breastfeeding, copious production of waxy material in ears, and inability to walk without an ambulatory aid (50%). Possible pathogenic mechanisms are discussed with respect to the clinicopathologic and genetic correlations observed.

Epidemiology of Darier's Disease in Slovenia.

AIM: To present a retrospective and prospective epidemiological and clinical study on Darier disease in Slovenia. RESULTS: Data on 77 DD patients was collected in the period 1973 to 2003 from the major dermatological departments and outpatient units in Slovenia. The prevalence of Darier disease in Slovenia is calculated at 3.8/100000 inhabitants. The ratio of affected/unaffected family members is 0.355. The comparison of two groups of DD patients (younger and older than 19 years) for the onset of the disease did not differ significantly although in two thirds of patients DD appeared for the first time before the age of 19 years. CONCLUSION: The epidemiological and clinical data on Darier's disease in Slovenia conform to similar reports with the exception of the higher prevalence of the disease in Slovenia. UV radiation seems to be an important triggering factor and therefore it is reasonable to advise DD patients to avoid sun exposure.

P160L mutation in the Ca(2+) ATPase 2A domain in a patient with severe Darier disease.

Darier disease (DD) is caused by mutations of the ATP2A2 gene, which encodes the sarco/endoplasmic reticulum Ca(2+)-ATPase isoform 2 (SERCA2). The mutations affect protein expression, degradation and activity. We report a patient with severe sporadic DD, who did not respond adequately to repeated courses of orally administered acitretin and isotretinoin. He was found to harbor the missense P160L mutation of the ATP2A2 gene in a heterozygous state in the A domain of SERCA2 and polymorphism in intron 18 (2741 + 54 G --> A). The A domain plays a key role in translocation of Ca(2+) from cytoplasm to endoplasmic reticulum lumen, thus establishing a low intracellular Ca(2+) concentration.