Mucosal Leukoplakia Research Articles

Cloning and characterization of Arabidopsis thaliana AtNAP57--a homologue of yeast pseudouridine synthase Cbf5p.

Rat Nap57 and its yeast homologue Cbf5p are pseudouridine synthases involved in rRNA biogenesis, localized in the nucleolus. These proteins, together with H/ACA class of snoRNAs compose snoRNP particles, in which snoRNA guides the synthase to direct site-specific pseudouridylation of rRNA. In this paper we present an Arabidopsis thaliana protein that is highly homologous to Cbf5p (72% identity and 85% homology) and NAP57 (67% identity and 81% homology). Moreover, the plant protein has conserved structural motifs that are characteristic features of pseudouridine synthases of the TruB class. We have named the cloned and characterized protein AtNAP57 (Arabidopsis thaliana homologue of NAP57). AtNAP57 is a 565 amino-acid protein and its calculated molecular mass is 63 kDa. The protein is encoded by a single copy gene located on chromosome 3 of the A. thaliana genome. Interestingly, the AtNAP57 gene does not contain any introns. Mutations in the human DKC1 gene encoding dyskerin (human homologue of yeast Cbf5p and rat NAP57) cause dyskeratosis congenita a rare inherited bone marrow failure syndrome characterized by abnormal skin pigmentation, nail dystrophy and mucosal leukoplakia.

Overlap of dyskeratosis congenita with the Hoyeraal-Hreidarsson syndrome

X-linked dyskeratosis congenita (DKC) is characterized by mucosal leukoplakia and ulcerations, skin abnormalities, nail dystrophy, and pancytopenia. Hoyeraal-Hreidarsson syndrome (HHS) includes intrauterine growth retardation, microcephaly, mental retardation, cerebellar malformation, and pancytopenia. A patient with striking features of both HHS and DKC has a de novo mutation in the DKC1 gene, known to be responsible for DKC. HHS may be a severe form of DKC, in which affected individuals die before characteristic mucocutaneous features develop. (J Pediatr 2000;136:390-3)

Molecular medicine and bone marrow failure syndromes

Molecular medicine and bone marrow failure syndromes

A Case of Dyskeratosis Congenita

A case of dyskeratosis congenita(DC) is reported. A 27-year-old man presented with generalized hyperpigmented macules and patches in reticulated or mottled pattern for 20 years, dystrophy of some fingernails and toenails, and mucosal leukoplakia on lips for 17 years. In addition, sparse and withered hairs, dental caries, and mild mental retardation were accompanied.

X-Linked Dyskeratosis Congenita Is Predominantly Caused by Missense Mutations in the DKC1 Gene

Dyskeratosis congenita is a rare inherited bone marrow-failure syndrome characterized by abnormal skin pigmentation, nail dystrophy, and mucosal leukoplakia. More than 80% of patients develop bone-marrow failure, and this is the major cause of premature death. The X-linked form of the disease (MIM 305000) has been shown to be caused by mutations in the DKC1 gene. The gene encodes a 514-amino-acid protein, dyskerin, that is homologous to Saccharomyces cerevisiae Cbf5p and rat Nap57 proteins. By analogy to the homologues in other species, dyskerin is predicted to be a nucleolar protein with a role in both the biogenesis of ribosomes and, in particular, the pseudouridylation of rRNA precursors. We have determined the genomic structure of the DKC1 gene; it consists of 15 exons spanning a region of 15 kb. This has enabled us to screen for mutations in the genomic DNA, by using SSCP analysis. Mutations were detected in 21 of 37 additional families with dyskeratosis congenita that were analyzed. These mutations consisted of 11 different single-nucleotide substitutions, which resulted in 10 missense mutations and 1 putative splicing mutation within an intron. The missense change A353V was observed in 10 different families and was shown to be a recurring de novo event. Two polymorphisms were also detected, one of which resulted in the insertion of an additional lysine in the carboxy-terminal polylysine domain. It is apparent that X-linked dyskeratosis congenita is predominantly caused by missense mutations; the precise effect on the function of dyskerin remains to be determined.

Reticulate hyperpigmentation.

Disorders that are characterized by a reticulate pattern of pigmentation are reviewed. Dyskeratosis congenita (DKC) is the prototype of these. In addition to reticulate hyperpigmentation, mucosal leukoplakia, bone marrow dysfunction, cytogenetic instability, and a predisposition to malignancy are characteristic of DKC. The most common pattern of inheritance is X-linked, with heterozygous females showing variable expression, most likely depending on tissue-specific patterns of random X-inactivation. Other reticulate pigmentary disorders reviewed include the Naegeli-Franceschetti-Jadassohn syndrome, X-linked reticulate pigmentary disorder, dermatopathia pigmentosa reticularis, Dowling-Degos disease, dyschromatosis, confluent and reticulated papillomatosis of Gougerot and Carteaud, reticulate acropigmentation of Kitamura, and Revescz syndrome. Diagnosis, treatment, and sometimes genetic counseling remain problematic for these entities. The pathophysiology of these disorders is unknown, but will certainly be aided greatly by the future identification of the underlying genes.

Dyskeratosis Congenita : Relationship to Fanconi's Anemia

Abstract Dyskeratosis congenita and Fanconi’s anemia share impressive features in common: primary refractory pancytopenia; bone marrow hyperplasia (curtailed phase) and megaloblastosis, eventuating in severe hypoplasia of the marrow; cutaneous melanotic dyschromia; lacrimal duct blockage and a host of other minor abnormalities, in addition to mental retardation and generalized impairment of growth. Evaluation of two brothers with dyskeratosis congenita, and review of previous reports, indicate the following to be more prominent in dyskeratosis congenita than in Fanconi’s anemia: cutaneous telangiectatic erythema and atrophy; exocrine, ungual, and dental dysplasias; mucosal leukoplakia, carcinomatosis, and stenosis; and esophageal diverticula. Prominent in Fanconi’s anemia but not dyskeratosis congenita are the renal and particular skeletal anomalies. Possible transition cases are discussed. The proband studied suffered from progressive refractory pancytopenia, fevers, abdominal pains, malabsorption syndrome, and finally subarachnoid hemorrhage. Cultured leukocytes had normal-appearing karyotypes. The proband’s brother had cutaneous alterations of dyskeratosis congenita, but a hemogram revealed only mild thrombocytopenia and macrocytosis. Both brothers had elevated levels of hemoglobin F, leukocyte alkaline phosphatase, serum IgG, and thyroglobulin antibody, and both had reduced levels of serum IgM and vitamin B12.