ABSTRACT
CAMOS (Cerebellar Ataxia with Mental retardation, Optic atrophy and Skin abnormalities) is a rare autosomal recessive syndrome characterized by a nonprogressive congenital cerebellar ataxia associated with mental retardation, optic atrophy, and skin abnormalities. Using homozygosity mapping in a large inbred Lebanese Druze family, we previously reported the mapping of the disease gene at chromosome 15q24-q26 to a 3.6-cM interval between markers D15S206 and D15S199. Screening of candidate genes lying in this region led to the identification of a homozygous p.Gly1046Arg missense mutation in ZNF592, in all five affected individuals of the family. ZNF592 encodes a 1267-amino-acid zinc-finger (ZnF) protein, and the mutation, located within the eleventh ZnF, is predicted to affect the DNA-binding properties of ZNF592. Although the precise role of ZNF592 remains to be determined, our results suggest that ZNF592 is implicated in a complex developmental pathway, and that the mutation is likely to disturb the highly orchestrated regulation of genes during cerebellar development, by either disrupting interactions with target DNA or with a partner protein.
Subject(s)
Chromosomes, Human, Pair 15 , DNA-Binding Proteins/genetics , Mutation, Missense , Zinc Fingers , Amino Acid Sequence , Chromosome Mapping , DNA-Binding Proteins/chemistry , DNA-Binding Proteins/metabolism , Disease Progression , Family Health , Gene Expression Regulation , Genes, Recessive , Genetic Linkage , Genetic Markers , Humans , Intellectual Disability/genetics , Lebanon , Molecular Sequence Data , Mutant Proteins/chemistry , Mutant Proteins/genetics , Mutant Proteins/metabolism , Spinocerebellar Degenerations/geneticsABSTRACT
Odonto-onycho-dermal dysplasia is a rare autosomal recessive syndrome in which the presenting phenotype is dry hair, severe hypodontia, smooth tongue with marked reduction of fungiform and filiform papillae, onychodysplasia, keratoderma and hyperhidrosis of palms and soles, and hyperkeratosis of the skin. We studied three consanguineous Lebanese Muslim Shiite families that included six individuals affected with odonto-onycho-dermal dysplasia. Using a homozygosity-mapping strategy, we assigned the disease locus to an ~9-cM region at chromosome 2q35-q36.2, located between markers rs16853834 and D2S353, with a maximum multipoint LOD score of 5.7. Screening of candidate genes in this region led us to identify the same c.697G-->T (p.Glu233X) homozygous nonsense mutation in exon 3 of the WNT10A gene in all patients. At the protein level, the mutation is predicted to result in a premature truncated protein of 232 aa instead of 417 aa. This is the first report to our knowledge of a human phenotype resulting from a mutation in WNT10A, and it is the first demonstration of an ectodermal dysplasia caused by an altered WNT signaling pathway, expanding the list of WNT-related diseases.
Subject(s)
Codon, Nonsense , Ectodermal Dysplasia/genetics , Nails, Malformed/genetics , Odontodysplasia/genetics , Wnt Proteins/genetics , Amino Acid Sequence , Base Sequence , Child, Preschool , Consanguinity , DNA/genetics , Female , Genes, Recessive , Humans , Lebanon , Male , Middle Aged , Pedigree , Syndrome , Tongue/abnormalitiesABSTRACT
Se estudiaron 114 niños con enuresis, a los que se les sometió estudios de examen general de orina y urocultivo. Los niños que presentaron bacteriuria, compatible con infección urinaria, se sometieron a estudios de cistograma miccional y de ultrasonido renal y de las vías urinarias. Los exámenes clínicos y de laboratorio no dieron datos de anormalidad en 109 niños; en cinco niñas se encontró evidencia de infección por E. coli, cuatro de ellas con síntomas clínicos compatibles con esta enfermedad. En ninguna de estas niñas se encontró alguna malformación de las vías urinarias que estuviese asociada a la infección, y ambos problemas con la enuresis. Se discuten estos hallazgos y se propone la secuencia de estudio, seguida en la investigación, para el manejo de los niños enuréticos
