RESUMO
Blindness due to retinal degeneration affects millions of people worldwide, but many disease-causing mutations remain unknown. PNPLA6 encodes the patatin-like phospholipase domain containing protein 6, also known as neuropathy target esterase (NTE), which is the target of toxic organophosphates that induce human paralysis due to severe axonopathy of large neurons. Mutations in PNPLA6 also cause human spastic paraplegia characterized by motor neuron degeneration. Here we identify PNPLA6 mutations in childhood blindness in seven families with retinal degeneration, including Leber congenital amaurosis and Oliver McFarlane syndrome. PNPLA6 localizes mostly at the inner segment plasma membrane in photoreceptors and mutations in Drosophila PNPLA6 lead to photoreceptor cell death. We also report that lysophosphatidylcholine and lysophosphatidic acid levels are elevated in mutant Drosophila. These findings show a role for PNPLA6 in photoreceptor survival and identify phospholipid metabolism as a potential therapeutic target for some forms of blindness.
Assuntos
Cegueira/genética , Mutação , Fosfolipases/genética , Fosfolipases/fisiologia , Sequência de Aminoácidos , Animais , Criança , Pré-Escolar , Drosophila , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microscopia de Fluorescência , Dados de Sequência Molecular , Linhagem , Fenótipo , Fosfolipídeos/química , Retina/patologia , Degeneração Retiniana/genética , Análise de Sequência de DNA , Homologia de Sequência de Aminoácidos , Espectrometria de Massas por Ionização por ElectrosprayRESUMO
PURPOSE: To investigate the transforming growth factor beta-induced gene (TGFBI) mutations in Brazilian patients with corneal dystrophy and to evaluate the phenotype-genotype correlation in these patients. METHODS: A total of 11 unrelated families were studied. The diagnosis of corneal dystrophy was based on clinical and histopathological findings. Genomic DNA was extracted from peripheral blood leucocytes, and exons 4 and 12 of the TGFBIgene were amplified by polymerase chain reaction followed by direct sequencing on both strands. RESULTS: Five different mutations in the TGFBIgene were found in the probands. We identified the following mutations: lattice corneal dystrophy--R124C and A546T; Reis-Bücklers corneal dystrophy--R555Q and R124L; granular corneal dystrophy--R555W and Avellino dystrophy--R555W. In three of the 11 studied families there was no mutation in exons 4 and 12. CONCLUSIONS: This is the first report of mutations in the TGFBIgene in a series of Brazilian patients with corneal dystrophy. The findings indicate that TGFBIgene screening should be considered in the diagnosis of corneal dystrophy.
Assuntos
Distrofias Hereditárias da Córnea/genética , Proteínas da Matriz Extracelular/genética , Mutação , Fator de Crescimento Transformador beta/genética , Sequência de Bases , Análise Mutacional de DNA/métodos , Humanos , Dados de Sequência Molecular , Reação em Cadeia da Polimerase/métodosRESUMO
OBJECTIVE: To evaluate a family with autosomal dominant optic atrophy, which has been previously linked to the Kidd blood group. DESIGN: Clinical evaluation with the assessment of visual acuity, color vision, and optic nerve appearance to determine affection status. Linkage analysis using polymorphic DNA markers. RESULTS: Visual acuities ranged from 20/20 to 6/200. Although linkage was excluded for chromosome 3q28-29, markers from chromosome 18 in the vicinity of the Kidd locus were linked to the disorder (D18S34 [maximal lod score (lodmax) of 5.38 at recombination fraction (theta) of 0.14], D18S548 [lod(max)=7.26, theta=0.09], D18S861 [lod(max)= 5.32, theta = 0.07], and D18S479 [lod(max) = 3.28, 0 = 0.12:]). Multipoint linkage analysis demonstrated lod scores of greater than 3 in an approximately 3-centimorgan region flanked by D18S34 and D18S479, using 98% penetrance and a phenocopy rate of 1/50. CONCLUSIONS: Dominant optic atrophy is genetically heterogeneous, with loci assigned to chromosomes 3q28-29 and 18q12.2-12.3. Dominant optic atrophy linked to 18q shows intrafamilial variation similar to that previously reported in families linked to 3q, with visual acuities ranging from normal to legal blindness. The overall distribution of visual acuities appears more favorable with the 18q phenotype. Both phenotypes appear to have a similar rate of visual decline.
Assuntos
Cromossomos Humanos Par 18/genética , Heterogeneidade Genética , Atrofias Ópticas Hereditárias/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Cromossomos Humanos Par 3/genética , Percepção de Cores/fisiologia , DNA/análise , Feminino , Ligação Genética/genética , Marcadores Genéticos , Genótipo , Humanos , Sistema do Grupo Sanguíneo Kidd/genética , Escore Lod , Masculino , Pessoa de Meia-Idade , Atrofias Ópticas Hereditárias/patologia , Atrofias Ópticas Hereditárias/fisiopatologia , Nervo Óptico/patologia , Linhagem , Acuidade Visual/fisiologiaRESUMO
A case of precocious puberty and diabetes insipidus in a 7 years old boy due to a malignant teratoma in the IVth ventricle is reported. The tumor had grown into the IIIrd and lateral ventricles as found on the necropsy. The original site of the tumor and the possible physiopathological mechanisms for the precocious puberty are discussed.
Assuntos
Neoplasias do Ventrículo Cerebral/complicações , Puberdade Precoce/etiologia , Teratoma/complicações , Neoplasias do Ventrículo Cerebral/patologia , Ventriculografia Cerebral/efeitos adversos , Criança , Diabetes Insípido/complicações , Humanos , Hipotálamo/fisiopatologia , Masculino , Teratoma/patologiaRESUMO
The authors report a case of large clivus chordoma in a 61/2-year-old child with multiple subarachnoid metastatic dissemination over the cerebellar hemispheres and spinal cord.