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1.
Hum Mutat ; 40(7): 938-951, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31067009

RESUMO

ALG3-CDG is one of the very rare types of congenital disorder of glycosylation (CDG) caused by variants in the ER-mannosyltransferase ALG3. Here, we summarize the clinical, biochemical, and genetic data of four new ALG3-CDG patients, who were identified by a type I pattern of serum transferrin and the accumulation of Man5 GlcNAc2 -PP-dolichol in LLO analysis. Additional clinical symptoms observed in our patients comprise sensorineural hearing loss, right-descending aorta, obstructive cardiomyopathy, macroglossia, and muscular hypertonia. We add four new biochemically confirmed variants to the list of ALG3-CDG inducing variants: c.350G>C (p.R117P), c.1263G>A (p.W421*), c.1037A>G (p.N346S), and the intron variant c.296+4A>G. Furthermore, in Patient 1 an additional open-reading frame of 141 bp (AAGRP) in the coding region of ALG3 was identified. Additionally, we show that control cells synthesize, to a minor degree, a hybrid protein composed of the polypeptide AAGRP and ALG3 (AAGRP-ALG3), while in Patient 1 expression of this hybrid protein is significantly increased due to the homozygous variant c.160_196del (g.165C>T). By reviewing the literature and combining our findings with previously published data, we further expand the knowledge of this rare glycosylation defect.


Assuntos
Defeitos Congênitos da Glicosilação/genética , Manosiltransferases/genética , Mutação , Peptídeo-N4-(N-acetil-beta-glucosaminil) Asparagina Amidase/deficiência , Animais , Células COS , Células Cultivadas , Pré-Escolar , Chlorocebus aethiops , Feminino , Humanos , Lactente , Masculino , Fases de Leitura Aberta , Peptídeo-N4-(N-acetil-beta-glucosaminil) Asparagina Amidase/genética , Polimorfismo de Nucleotídeo Único
2.
Mol Genet Metab ; 123(3): 364-374, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29396028

RESUMO

Congenital disorders of glycosylation (CDG) are genetic defects in the glycoconjugate biosynthesis. >100 types of CDG are known, most of them cause multi-organ diseases. Here we describe a boy whose leading symptoms comprise cutis laxa, pancreatic insufficiency and hepatosplenomegaly. Whole exome sequencing identified the novel hemizygous mutation c.542T>G (p.L181R) in the X-linked ATP6AP1, an accessory protein of the mammalian vacuolar H+-ATPase, which led to a general N-glycosylation deficiency. Studies of serum N-glycans revealed reduction of complex sialylated and appearance of truncated diantennary structures. Proliferation of the patient's fibroblasts was significantly reduced and doubling time prolonged. Additionally, there were alterations in the fibroblasts' amino acid levels and the acylcarnitine composition. Especially, short-chain species were reduced, whereas several medium- to long-chain acylcarnitines (C14-OH to C18) were elevated. Investigation of the main lipid classes revealed that total cholesterol was significantly enriched in the patient's fibroblasts at the expense of phophatidylcholine and phosphatidylethanolamine. Within the minor lipid species, hexosylceramide was reduced, while its immediate precursor ceramide was increased. Since catalase activity and ACOX3 expression in peroxisomes were reduced, we assume an ATP6AP1-dependent impact on the ß-oxidation of fatty acids. These results help to understand the complex clinical characteristics of this new patient.


Assuntos
Defeitos Congênitos da Glicosilação/genética , Cútis Laxa/genética , Insuficiência Pancreática Exócrina/genética , Metaboloma/genética , ATPases Vacuolares Próton-Translocadoras/genética , Acil-CoA Oxidase/metabolismo , Catalase/metabolismo , Defeitos Congênitos da Glicosilação/diagnóstico , Defeitos Congênitos da Glicosilação/metabolismo , Cútis Laxa/diagnóstico , Cútis Laxa/metabolismo , Insuficiência Pancreática Exócrina/diagnóstico , Insuficiência Pancreática Exócrina/metabolismo , Ácidos Graxos/metabolismo , Genes Ligados ao Cromossomo X/genética , Humanos , Lactente , Masculino , Metabolômica , Oxirredução , ATPases Vacuolares Próton-Translocadoras/deficiência , Sequenciamento do Exoma
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