Search

CARD14-associated papulosquamous eruption (CAPE) is a proposed term that encompasses features ranging from psoriasis to pityriasis rubra pilaris (PRP) in association with CARD14 mutations. The early onset of the disease, prominent facial involvement, family history of an autosomal dominant trait, and poor response to conventional treatment are characteristics of CAPE that distinguish it from classical psoriasis and PRP. We describe the clinical features, family history, and response to therapy in three unrelated children with CAPE and compare these characteristics with those of previously described pediatric patients. Testing for CARD14 mutations in children with early onset of features of psoriasis or pityriasis rubra pilaris and resistance to conventional therapy should be considered.

Congenital vertical talus (CVT) is a primary dislocation of the talonavicular joint that often occurs in neuromusculoskeletal syndromes, but may also be seen as an isolated abnormality. Six families with isolated CVT were ascertained. DNA was isolated from 21 affected individuals and 17 unaffected individuals from these families, as well as from five sporadic patients with CVT. Variable expressivity was noted in three families, manifesting as clubfoot in three individuals. Genome-wide linkage analysis generated a maximum two-point logarithm of odds score on chromosome 2q with D2S1353 (Zmax = 1.43 at theta(max) = 0.1), 17 Mb from the HOXD gene cluster. DNA from one affected individual of each family was subjected to mutational analysis of the HOXD10 gene. A single missense mutation was identified (M319K, 956T > A) in the homeodomain recognition helix of the HOXD10 gene that segregated with disease in one large British family. This mutation was recently described in a family of Italian descent with CVT and Charcot-Marie-Tooth deformity HOXD10 gene mutations were not identified in any of the other families or sporadic patients with CVT, suggesting that genetic heterogeneity underlies this disorder.

We identified a family where five members had nonsyndromic ectrodactyly. There were three known instances of nonpenetrance. Although four individuals had unilateral cleft hand, one individual had more severe, bilateral and asymmetric absence of the digits. None had foot abnormalities. After exclusion of linkage of SHFM in this family to five known loci, a genome wide scan was performed with DNA from 5 affected and 15 unaffected members of this family. Suggestive evidence for linkage of ectrodactyly to 8q was obtained on the basis of a maximum LOD score of 2.54 at theta (max) = 0 with GAAT1A4. Critical recombinants place the ectrodactyly gene in this family in a 16 cM (21 Mb) interval between D8S1143 and D8S556. Mutational analysis of two candidate genes (FZD6, GDF6) did not identify any mutations in affected members of this family. Our data indicate further genetic heterogeneity for ectrodactyly and suggest the presence of an additional SHFM locus in chromosome region 8q21.11-q22.3.

Isolated foot anomalies, including congenital vertical talus, were shown recently to occur in heterozygous carriers of CDMP-1 (cartilage-derived morphogenetic protein-1) gene mutations. Six families with isolated congenital vertical talus with apparent autosomal dominant inheritance were ascertained. DNA was isolated from 17 affected individuals and 24 unaffected individuals from these families and subjected to mutational analysis of the CDMP-1 gene. A missense mutation was identified (1312C>T) that results in an R438C substitution in the CDMP-1 active domain. This segregated with disease in one Northeren American family. Phenotypic variability in this family includes brachydactyly type C, clinodactyly, calcaneo valgus deformity, and congenital vertical talus. Metacarpophalangeal profiles (MCPPs) confirm incomplete penetrance in one family member. Hence, CDMP-1 mutations may be found in individuals with apparently isolated CVT, although careful examination of family members may reveal additional, subtle hand and foot abnormalities. However, mutations in CDMP-1 do not appear to be a frequent cause of isolated congenital vertical talus.

Psoriasis is an inflammatory, immune-mediated disease of the skin. Several studies have suggested that natural killer (NK) cells and their receptors may be important for its pathogenesis. Here, we examined whether deletion of the activating natural killer receptor gene NKG2C, which has a frequency of 20% in the European population, was associated with psoriasis susceptibility. The NKG2C deletion and a functional polymorphism in its ligand HLA-E were genotyped in a Caucasian cohort of 611 psoriasis cases and 493 controls. We found that the NKG2C deletion was significantly increased in cases compared with controls [0.258 vs 0.200, P = 0.0012, OR = 1.43 (1.15-1.79)]. The low-expressing HLA-E*01:01 allele was associated with psoriasis (P = 0.0018), although this association was dependent on HLA-C. Our findings support a potential immunoregulatory role for NK cells in psoriasis and suggest the importance of future studies to investigate the contribution of NK cells and their regulatory receptors to the pathogenesis of psoriasis.

Objective To localize the gene for familial recurrent arthritis via a genome-wide linkage scan in an extended kindred with the disease. Methods A 3-generation family in which 9 members were diagnosed with juvenile idiopathic arthritis (JIA) was ascertained. In this family the disease was of very early onset and included episodic inflammation leading to eventual destruction of joints, muscle, and skin. We treated this disorder as a distinct clinical entity that we have named “familial recurrent arthritis.” A genome-wide linkage scan with polymorphic microsatellites at 10–15-cM resolution was initiated. Results The genome-wide scan generated a maximum 2-point logarithm of odds score with D15S211 (Zmax = 3.27 at θmax= 0.0010). Haplotype reconstruction defined a candidate region of ∼20 cM flanked proximally by D15S983 and distally by D15S127 on human chromosome 15. Conclusion A gene for familial recurrent arthritis was localized to 15q22-24, as a result of a genome-wide linkage scan in a large, multiply affected kindred. Identification of the altered gene will provide insights into the pathogenesis of autoimmune joint destruction that is reminiscent of JIA.

Explanted cells from salivary gland tumors are particularly difficult to propagate in vitro and not efficiently immortalized by agents such as simian virus 40. Human papillomavirus 16 (HPV16) has been widely used to transform cells of epithelial origin, but its use for salivary gland cell transformation has not been described. In this study, we employed viral constructs containing the E6/E7 genes of HPV16 to infect and stably transform 9 salivary gland tumor cell cultures. Four of the tumor cell cultures were derived from benign tumors and 5 from malignant tumors. All of the original cell cultures were diploid; however, 6 contained subpopulations of cells with structural abnormalities. All 9 cell cultures were successfully transformed, and 8 were immortalized. The resulting cell lines have decreased serum requirements, exhibit a high proliferation rate, are E6/E7-positive and form colonies in soft agar. Immuno-histochemical and molecular studies confirmed that the transformed cells were indeed epithelial/myoepithelial in origin. All of the transformed cell lines had a diploid or near-diploid karyotype, and 2 contained the original translocated chromosomes in all cells. Our report represents a new application of the E6/E7 system in immortalizing salivary gland cell cultures, resulting in retention of the cellular features found in the native tissue without a general destabilization of the karyotype. These types of tissue culture resources should prove useful for positional cloning and functional studies of genes involved in salivary gland oncogenesis.

SUMMARY Clinical and family history data on persons affected with Wilson disease (WD) living in Israel between 1958 and 1984 were ascertained from the literature, hospital records and neurological and gastroenterological clinics. From this population of 51 families, representing a diversity of Middle Eastern, North African and European backgrounds, blood samples were collected from affected individuals in 21 families, their parents, sibs and other relatives for quantitative determinations of plasma copper and ceruloplasmin, liver tests and DNA analysis. Although the majority of patients have the hepatic form of the disease, hepatic and neurological cases were found among all ethnic groups. In fact, affected sibs in several inbred families who most likely inherited two copies of the same mutant allele had different symptoms. Gene frequencies were calculated for each of the populations taking into account inbreeding, probability of ascertainment, and estimated incidence. Although many of these communities have gene frequencies which are comparable to worldwide estimates, high prevalence of disease is maintained by consanguineous mating patterns. Probabilities of WND genotypes were calculated for 129 unaffected relatives who had an a priori risk of inheriting at least one WND allele using information from 10 DNA markers closely linked to the WND locus. There was no evidence that multiple loci are responsible for the observed clinical variability in this sample of families. Furthermore, studies of serum copper and ceruloplasmin levels in unaffected relatives suggest that phenotypic variability in WD may be due in part to an interaction of the WND locus with other genetic or non-genetic modifiers such as age.