RESUMO
Papillon-Lefèvre syndrome (PLS) is an autosomal recessive palmoplantar keratoderma caused by cathepsin C (CTSC) gene mutations. This study reports CTSC mutational and enzyme analyses in a consanguineous Brazilian family with PLS, representing the first enzymatic analysis of a Brazilian kinship with PLS. This family segregates a novel PLS-related mutation, p.W185X, that is associated with a complete loss of enzymatic activity.
Assuntos
Catepsina C/genética , Doença de Papillon-Lefevre/genética , Mutação Puntual , Sequência de Aminoácidos , Substituição de Aminoácidos , Animais , Sequência de Bases , Brasil , Consanguinidade , Sequência Conservada , DNA/genética , Análise Mutacional de DNA , Feminino , Heterozigoto , Homozigoto , Humanos , Masculino , Linhagem , Homologia de Sequência de Aminoácidos , Especificidade da EspécieRESUMO
A genotype-phenotype analysis of a three-generation family segregating for an autosomal-dominant osteogenesis imperfecta (OI) variant is reported here. The family was ascertained through the presentation of a proband concerned about discoloration of her teeth, found to be dentinogenesis imperfecta (DGI). Examination of 36 family members identified 15 individuals with DGI. Linkage studies were performed for genetic markers from candidate intervals known to contain genes responsible for DGI on chromosomes 4q, 7q, and 17q. Conclusive evidence for linkage of DGI was obtained to genetic markers on chromosome 17q21-q22 (DLX-3, Z(max) = 5.34, theta = 0.00). All DGI-affected family members shared a common haplotype, which was not present in individuals without DGI. Haplotype analysis sublocalized the gene to a 5-cM genetic interval that contained the collagen 1 alpha 1 (COL1A1) gene. More than 150 different COL1A1 gene mutations have been associated with various forms of OI, and five of these have been associated with DGI and type IV OI. After excluding these five mutations, mutational analysis was performed on the remaining exons including intron--exon boundaries, which resulted in identification of a Gly559Cys mutation in exon 32, present in all DGI-affected family members. Clinical features segregating with this G559C mutation included hyperextensible joints, joint pain and an increased propensity for bone fractures with moderate trauma. This is the first report of joint pain associated with a COL1A1 mutation and DGI. The mild skeletal features and reduced penetrance of the non-dental findings illustrate the importance of genetic evaluations for families with a history of DGI.
Assuntos
Cromossomos Humanos Par 17/genética , Colágeno Tipo I , Colágeno/genética , Dentinogênese Imperfeita/genética , Osteogênese Imperfeita/genética , Substituição de Aminoácidos , Brasil , Cadeia alfa 1 do Colágeno Tipo I , Cisteína/genética , Análise Mutacional de DNA , Feminino , Glicina/genética , Humanos , Instabilidade Articular/genética , Escore Lod , Masculino , Mutação de Sentido Incorreto , LinhagemRESUMO
Neonatal screening for profound biotinidase deficiency (less than 10% of the mean normal activity level) has identified a group of children with partial biotinidase deficiency (10% to 30% of mean normal activity). Because partial biotinidase deficiency may result in clinical consequences that may be prevented by treatment with biotin, we evaluated such individuals and their family members (1) to determine whether partial biotinidase deficiency is associated with symptoms and (2) to determine the inheritance pattern. We quantified serum biotinidase activity levels and obtained medical histories of probands, their parents and siblings, and additional family members. All children with partial deficiency were healthy at the time of diagnosis. One child, who was not initially treated with biotin, later developed hypotonia, hair loss, and skin rash, which resolved with biotin therapy. Four adults and three children with partial biotinidase deficiency were identified among family members of infants identified by neonatal screening. All these individuals were healthy, although one sibling had elevated urinary lactate excretion. A fifth adult with partial deficiency, found among clinically normal adult volunteers, later showed minor symptoms that resolved after biotin therapy. Like children with profound biotinidase deficiency, children with partial biotinidase deficiency are symptoms free at birth. However, the subsequent occurrence of symptoms of profound biotinidase deficiency in some persons with partial deficiency suggests that biotin therapy for this condition may be warranted.