Novel mutations of the BSCL2 and AGPAT2 genes in 10 families with Berardinelli-Seip congenital generalized lipodystrophy syndrome.

CONTEXT: Congenital generalized lipodystrophy, or Berardinelli-Seip syndrome, is a rare autosomal recessive disease caused by mutations in either the BSCL2 or AGPAT2 genes. This syndrome is characterized by an almost complete loss of adipose tissue usually diagnosed at birth or early infancy resulting in apparent muscle hypertrophy. Common clinical features are acanthosis nigricans, hepatomegaly with or without splenomegaly and high stature. Acromegaloid features, cardiomyopathy and mental retardation can also be present. DESIGN: We investigated 11 kindreds from different geographical areas of Brazil (northeast and southeast). All coding regions as well as flanking intronic regions of both genes were examined. Polymerase chain reaction (PCR) amplifications were performed using primers described previously and PCR products were sequenced directly. RESULTS: Four AGPAT2 and two BSCL2 families harboured the same set of mutations. BSCL2 gene mutations were found in the homozygous form in four kindreds (c.412C>T c.464T>C, c.518-519insA, IVS5-2A>G), and in two kindreds compound mutations were found (c.1363C>T, c.424A>G). In the other four families, one mutation of the AGPAT2 gene was found (IVS3-1G>C and c.299G>A). CONCLUSIONS: We have demonstrated four novel mutations of the BSCL2 and AGPAT2 genes responsible for Berardinelli-Seip syndrome and Brunzell syndrome (AGPAT2-related syndrome).

Molecular analysis of the WNT4 gene in 6 patients with Mayer-Rokitansky-Küster-Hauser syndrome.

Molecular analysis of the WNT4 gene in 6 patients with Mayer-Rokitansky-Küster-Hauser syndrome without androgen excess excluded this gene as a major cause of this syndrome, regardless of the subtype.

A signal peptide mutation of the arginine vasopressin gene in monozygotic twins.

Familial neurohypophysial diabetes insipidus (FNDI) is a rare autosomal dominant syndrome stemming from the absence of arginine vasopressin (AVP). More than thirty-five different germline mutations in the arginine vasopressin-neurophysin II gene have been reported. These mutations are either in the signal peptide or scattered throughout the neurophysin II domain. A missense mutation altering alanine at position -1 to either valine or threonine in the signal peptide domain has previously been found in ten unrelated families. In the present report, Brazilian female monozygotic twins with clinically typical central DI in whom biochemical and molecular characterization were carried out are described. Direct mutational analysis by sequencing of the vasopressin gene in germline DNA revealed a heterozygous missense mutation (G-->A) at nucleotide 279, predicting the substitution of alanine by threonine at position -1 of the signal peptide moiety. In summary, we present an extremely rare case of familial central diabetes insipidus in monozygotic Brazilian twins with a seemingly common missense mutation in the AVP gene.

A novel mutation of the cathepsin C gene in Papillon-Lefèvre syndrome.

BACKGROUND: Papillon-Lefèvre syndrome (PLS) is a disorder that involves destruction of the periodontium and abnormal hyperkeratosis of the palms of the hands and soles of the feet. Mutations of the lysosomal protease cathepsin C gene (CTSC) have been associated with PLS. However, genotypic and phenotypic correlation has not been established. In the present study we investigated the CTSC gene in a Brazilian cohort affected by PLS. METHODS: Eight consanguineous members of a kindred with PLS were studied. DNA was extracted and all exons of the gene amplified by the polymerase chain reaction (PCR) using specific primers. Mutations were identified by DNA sequencing of the coding region and introns of the CTSC gene. RESULTS: Sequence analysis of CTSC from subjects affected by PLS identified a novel mutation (587T --> C) in exon 4, predicted to cause a Leu196Pro amino acid substitution. Three of 3 subjects were homozygous for cathepsin C mutations inherited from a common ancestor. One patient was heterozygous and showed plantar hyperkeratosis without periodontal disease. Two other family members were also heterozygous but did not present palmoplantar hyperkeratosis and/or periodontal disease. CONCLUSIONS: This study describes a novel mutation of the cathepsin C gene in a Brazilian kindred with Papillon-Lefèvre syndrome.

A Novel Mutation of the Cathepsin C Gene in Papillon-Lefévre Syndrome.

BACKGROUND: Papillon-Lefévre syndrome (PLS) is a disorder that involves destruction of the periodontium and abnormal hyperkeratosis of the palms of the hands and soles of the feet. Mutations of the lysosomal protease cathepsin C gene (CTSC) have been associated with PLS. However, genotypic and phenotypic correlation has not been established. In the present study we investigated the CTSC gene in a Brazilian cohort affected by PLS. METHODS: Eight consanguineous members of a kindred with PLS were studied. DNA was extracted and all exons of the gene amplified by the polymerase chain reaction (PCR) using specific primers. Mutations were identified by DNA sequencing of the coding region and introns of the CTSC gene. RESULTS: Sequence analysis of CTSC from subjects affected by PLS identified a novel mutation (587T → C) in exon 4, predicted to cause a Leu196Pro amino acid substitution. Three of 3 subjects were homozygous for cathepsin C mutations inherited from a common ancestor. One patient was heterozygous and showed plantar hyperkeratosis without periodontal disease. Two other family members were also heterozygous but did not present palmoplantar hyperkeratosis and/or periodontal disease. CONCLUSIONS: This study describes a novel mutation of the cathepsin C gene in a Brazilian kindred with Papillon-Lefévre syndrome. J Periodontol 2002;73:307-312.

Diabetes insipidus nefrogênico: conceitos atuais de fisiopatologia e aspectos clínicos / Nephrogenic diabetes insipidus: actual concepts of fisiopathology and clinical aspects

O diabetes insipidus nefrogênico (DIN) é uma doença rara caracterizada pela incapacidade do rim de concentrar a urina, a despeito de concentrações normais ou aumentadas do hormônio antidiurético arginina-vasopressina (AVP). Recentes avanços da fisiopatologia renal mostraram que, após a ligação do AVP ao seu receptor AVPR2 (receptor de vasopressina tipo 2), uma cascata de eventos culmina com a reabsorção de água no túbulo coletor, por meio de canais permeáveis exclusivamente à água e localizados nas membranas apicais do túbulo coletor, sendo o mais importante deles a aquaporina-2 (AQP2). A identificação, caracterização e análise mutacional dos genes AVPR2 e AQP2 permitiram estabelecer as bases moleculares de vários tipos hereditários de diabetes insipidus nefrogênico. Aproximadamente 90 por cento desses pacientes apresentam mutações do AVPR2, 8 por cento apresentam mutações no AQP2 e o restante não tem causas identificadas. Nessa revisão apresentamos exemplos de alterações genéticas e sugerimos que o uso de técnicas de biologia molecular pode minimizar as complicações dessa doença heterogênea mas com fenótipo bastante semelhante.

Analise de mutações somáticas dos genes APP, presenilina 1 e 2, em tecido encefálico na doença de Alzheimer / Somatic mutationals analysis of genes APP, presenilin 1 and 2, in encephalic tissue in Alzheimer's disease

As bases moleculares da forma esporadica da doenca de Alzheimer (DA) permanecem ainda desconhecidas. Nos formulamos a hipotese de que, em alguns casos esporadicos de DA, uma mutacao somatica nos genes da proteina precursora amiloide (APP), da presenilina 1 (PS-1) e 2 (STM2) (genes envolvidos na DA forma familiar) em uma celula embrionaria comprometida com o desenvolvimento neuronal, pode resultar em fenotipo da DA. Usando a tecnica de PCR, eletroforese em gel de gradiente desnaturante (DGGE), analise de restricao e sequenciamento direto de DNA, nos analisamos esses genes em 99 tecidos encefalicos de pacientes com DA comprovada histologicamente. Uma amostra de tecido encefalico mostrou uma mutacao no gene PS-1 (His 163 Arg), que mais tarde foi demonstrada ser uma mutacao de celulas germinativas. Nenhuma outra anormalidade de migracao foi demonstrada, em qualquer amostra, nos exons 16 ou 17 do gene APP, nos exons codificadores da PS-1 ou qualquer padrao anormal de digestao pela analise de restricao no gene PS-2...