RESUMO
Pompe disease, or glycogen storage disease type II (GSD2), an autosomal recessive disease first described by Joannes Cassianus Pompe (1901-1945), causes deficient activity of acid α-glucosidase (GAA) enzyme. GAA catalyses α 1,4 and α 1,6 glucosidic linkages in lysosomes; destruction of these linkages permits glycogen to be separated into glucose and later used for energy. Without proper function of this enzyme, glycogen accumulates in lysosome, causing muscle hypotonia. We report a previously undescribed association of c.1437G>A intron 9 substitution on the GAA gene with severe infantile-onset Pompe disease in a deceased proband and carrier status in four of five surviving family members. Previous authors have found late-onset or moderate severity infantile-onset Pompe disease associated with this allelic variation. Our proband's family's village was suspicious for locally endemic disease. While our proband developed all features of classic infantile onset GSD2, socioeconomic and geographic factors initially suggested an infectious aetiology.
Assuntos
Genótipo , Doença de Depósito de Glicogênio Tipo II/genética , Glicogênio/metabolismo , Íntrons , Fenótipo , Mutação Puntual , alfa-Glucosidases/genética , Alelos , Família , Triagem de Portadores Genéticos , Humanos , Lactente , Lisossomos/metabolismo , Masculino , Hipotonia Muscular/genética , Polimorfismo de Nucleotídeo ÚnicoRESUMO
A novel microdeletion of 14q13.1q13.3 was identified in a patient with developmental delay and intractable epilepsy. The 2.2-Mb deletion included 15 genes, of which TULIP1 (approved gene symbol: RALGAPA1)was the only gene highly expressed in the brain. Western blotting revealed reduced amount of TULIP1 in cell lysates derived from immortalized lymphocytes of the patient, suggesting the association between TULIP1 haploinsufficiency and the patient's phenotype, then 140 patients were screened for TULIP1 mutations and four missense mutations were identified. Although all four missense mutations were common with parents, reduced TULIP1 was observed in the cell lysates with a P297T mutation identified in a conserved region among species. A full-length homolog of human TULIP1 was identified in zebrafish with 72% identity to human. Tulip1 was highly expressed in zebrafish brain, and knockdown of which resulted in brain developmental delay. Therefore, we suggest that TULIP1 is a candidate gene for developmental delay.
Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 14/genética , Deficiências do Desenvolvimento/genética , Epilepsia Generalizada/genética , Proteínas Ativadoras de GTPase/deficiência , Mutação de Sentido Incorreto , Proteínas do Tecido Nervoso/deficiência , Sequência de Aminoácidos , Animais , Encéfalo/anormalidades , Encéfalo/embriologia , Criança , Cromossomos Humanos Par 14/ultraestrutura , Códon/genética , Sequência Conservada , Feminino , Proteínas Ativadoras de GTPase/genética , Proteínas Ativadoras de GTPase/fisiologia , Técnicas de Silenciamento de Genes , Humanos , Deficiência Intelectual/genética , Masculino , Dados de Sequência Molecular , Hipotonia Muscular/genética , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/fisiologia , Linhagem , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos , Peixe-Zebra/embriologia , Peixe-Zebra/genética , Proteínas de Peixe-Zebra/deficiência , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/fisiologiaRESUMO
From the investigation by microarray-based comparative genomic hybridization (aCGH), a new syndrome with "atypical" proximal interstitial deletion of 1p36.23-36.11 has been suggested. Here, we report on an 8.5-year-old girl with psychomotor developmental delay and a dysmorphic appearance. Although her G-banded chromosomal analysis showed inv(3)(p14.1q26.2), detailed FISH analyses denied pathogenic deletions around the breakpoints of chromosome 3. Accordingly, aCGH analysis was performed to identify a genomic aberration related to her phenotype, and a 3.5-Mb interstitial deletion of 1p36.13-36.12 was revealed. This deletion was the most proximal interstitial deletion of 1p36. Compared to the previously reported patients, abnormally shaped teeth, delayed tooth eruption, and leg malformation are unique phenotypes only to this patient, which might be due to the centromeric unique deletion region with 0.8-Mb.
Assuntos
Anormalidades Múltiplas/genética , Deleção Cromossômica , Cromossomos Humanos Par 1/genética , Cromossomos Humanos Par 3 , Criança , Inversão Cromossômica , Mapeamento Cromossômico , Anormalidades Craniofaciais/diagnóstico , Anormalidades Craniofaciais/genética , Feminino , Humanos , Hibridização in Situ Fluorescente , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Hipotonia Muscular/diagnóstico , Hipotonia Muscular/genética , Análise de Sequência com Séries de Oligonucleotídeos , Fenótipo , SíndromeRESUMO
Chromosomal 8p23 deletion syndrome is recognized as a malformation syndrome with clinical symptoms of facial anomalies, microcephaly, mental retardation, and congenital heart defects. The responsible gene for the heart defects in this syndrome has been identified as GATA4 on 8p23.1. Two patients with interstitial deletions of 8p23.1 were investigated; one patient showed moderate developmental delay and Ebstein anomaly, and the other showed mild delay and typical atrioventricular septum defect. The precise deletion sizes, 17 and 2.9 Mb, were determined by FISH analyses using BAC clones as probes. The latter deletion was the smallest deletion including GATA4 in the previously reported patients, and the critical regions and genes for clinical manifestation of 8p23 deletion syndrome, including facial anomalies, microcephaly, behavioral abnormality, and developmental delay, were discussed.