Evidence for Extensive Locus Heterogeneity in Naxos Disease

4 páginas, 1 figura, 1 tabla.In this study, we report the clinical findings in two new Arab families with Naxos disease originating from villages near Jerusalem. Importantly, we have excluded both plakoglobin and desmoplakin as the candidate genes in these families. Furthermore, we have analyzed several other regions harboring candidate genes of interest, and found no evidence for linkage.This work was supported in part by the USPHS NIH NIAMS Grant R01 AR44924 and K02 AR 02047 (A.M.C) and a pilot and feasibility study within the Columbia University Skin Disease Research Center P30 AR44535 (to A.M.C and A.Z) and grant from the joint research fund of the Hebrew University and Hadassah (L.H).Peer reviewe

Multiple Cutaneous and Uterine Leiomyomas: Refinement of the Genetic Locus for Multiple Cutaneous and Uterine Leiomyomas on Chromosome 1q42.3–43

13 páginas, 2 figuras, 1 tabla.Cutaneous leiomyomas, rare benign tumors originating from the arrector pili muscle of the hair follicle, can be associated with the common uterine fibroids in a syndrome called multiple cutaneous and uterine leiomyomas. Multiple cutaneous and uterine leiomyomas are inherited as an autosomal dominant trait, providing an excellent opportunity for the study of the common non-Mendelian manifestation of isolated uterine fibroids. This study reports the clinical and molecular characterization of an extended family with multiple cutaneous and uterine leiomyomas. Linkage analysis has shown that the disease in this family is linked to the recently reported genetic locus for multiple cutaneous and uterine leiomyomas, with a maximum two-point LOD score of 4.453 for markers D1S2670, D1S2785, D1S547, and D1S1609. The identification of key recombination events has allowed us to refine substantially the location of the genetic locus for multiple cutaneous and uterine leiomyomas, from 14 cM to an interval of 4.55 or 7.19 cM, depending on the final phenotype of a young family member in which one of the key recombination events has occurred. In addition, we provide a description of the interesting pattern and progression of the skin phenotype in this four-generation kindred. The refinement of the genetic locus for multiple cutaneous and uterine leiomyomas and the availability of an extended multigeneration pedigree will facilitate the identification of the mutated gene responsible for multiple cutaneous and uterine leiomyomas, which, in turn, may provide key information for the understanding of the molecular basis of the common uterine fibroids.This study was supported in part by the Skin Disease Research Center, Department of Dermatology, Columbia University (P30 AR44535) and research grants K01-HG00055-01 (to D.G.), HG00008 (to J.O.) from the National Institutes of Health and a research grant from the Women's Health Program, supported by HWZOA (to A.Z.).Peer reviewe

Identification of mutations in the COL7A1 gene in a proband with mild recessive dystrophic epidermolysis bullosa and aortic insufficiency

12 páginas, 2 figuras.We report the clinical and molecular findings in a patient with a mild form of recessive dystrophic epidermolysis bullosa and aortic insufficiency. To our knowledge, this is the first report of association between dystrophic epidermolysis bullosa and abnormalities of the aortic valve. Analysis of the COL7A1 gene has revealed two new mutations, a 20-bp duplication and a splice site mutation.This study was supported by NIH NIAMS R01 AR43602 (A.M.C.).Peer reviewe

Mutations in lipase H cause autosomal recessive hypotrichosis simplex with woolly hair

Mutations in lipase H ( LIPH) are a rare cause of autosomal recessive hypotrichosis (HT) simplex. In this study, we investigated the clinical and molecular basis of HT simplex with woolly hair in 3 nonrelated families. Three families of Jewish, Arab Muslim, and Italian origin that presented with HT with woolly hair were studied. The phenotype was confirmed by clinical, microscopic, and histologic examination. Polymorphic microsatellite genotyping and direct automated DNA sequencing of the LIPH gene were used to identify the mutations in our probands. All patients had woolly hair since birth. At presentation, scalp hair density was reduced or normal. Sequencing of the LIPH gene revealed two homozygous mutations: a large recurrent 90-base pair duplication mutation in exon 2 in the Jewish and Arab families, and a novel deletion/insertion mutation in exon 4 in the Italian family. Only 3 families were studied. Mutations in LIPH result in variable degrees of HT. Woolly hair is an essential component of the clinical spectrum. A hot spot in the LIPH gene may be c.280_369dup in exon 2

De novo mutations in monilethrix

4 páginas, 1 figura.Mutations in the hair keratins hHb1 and hHb6 have been recently reported to cause monilethrix, an autosomal dominant hair shaft disorder, characterized by variable degrees of hair fragility and follicular hyperkeratosis. We found 10 families with monilethrix in which the parents were not clinically affected, and sequenced the hair keratin hHb1, hHb3 and hHb6 genes in seven patients. In five patients no mutations were found, while in two patients we identified de novo germline missense mutations at the helix termination motif: E402K (hHb6) and E413K (hHb1).This work was supported in part by the National Alopecia Areata Foundation (AZ).Peer reviewe

Germline Fumarate Hydratase Mutations in Families with Multiple Cutaneous and Uterine Leiomyomata

9 páginas, 2 figuras, 2 tablas.Germline mutations in the fumarate hydratase gene (FH) predispose to multiple cutaneous and uterine leiomyoma syndrome (MCL) and MCL associated with renal cell cancer. MCL is inherited in an autosomal dominant pattern, manifesting as skin leiomyoma and uterine fibroids in affected individuals. Fumarate hydratase, a component of the tricarboxylic acid cycle, acts as a tumor suppressor gene in the development of cutaneous and uterine leiomyoma and renal cell cancer in this syndrome. Here we report the clinical and mutational analysis of five families with MCL, with the identification of five new mutations affecting highly conserved residues of the FH protein. These results provide further evidence for the role of the FH gene in the pathogenesis of MCL.This work was supported in part by the Skin Disease Research Center, Department of Dermatology, Columbia University (P30 AR44535); a research grant K01-HG0005501 (to D.G.); and a research grant from the Women's Health Program, supported by HWZOA (to A.Z. and B.G.). G.S.C. is a Medical Student Research Training Fellow of Howard Hughes Medical Institute.Peer reviewe

Identification of distinct mutations in AAGAB in families with type 1 punctate palmoplantar keratoderma

This study was supported in part by funding from the NIH/NIAMS (R01-AR44924) to AMC. MF is a trainee on NIH/NIGMS T32GM082771, Medical Genetics Training Program.Peer Reviewe

Correction: MicroRNAs Expression in the Ileal Pouch of Patients with Ulcerative Colitis Is Robustly Up-Regulated and Correlates with Disease Phenotypes.

[This corrects the article DOI: 10.1371/journal.pone.0159956.]