Three rare diseases in one Sib pair: RAI1, PCK1, GRIN2B mutations associated with Smith-Magenis Syndrome, cytosolic PEPCK deficiency and NMDA receptor glutamate insensitivity.
Mol Genet Metab
; 113(3): 161-70, 2014 Nov.
Article
em En
| MEDLINE
| ID: mdl-24863970
ABSTRACT
The National Institutes of Health Undiagnosed Diseases Program evaluates patients for whom no diagnosis has been discovered despite a comprehensive diagnostic workup. Failure to diagnose a condition may arise from the mutation of genes previously unassociated with disease. However, we hypothesized that this could also co-occur with multiple genetic disorders. Demonstrating a complex syndrome caused by multiple disorders, we report two siblings manifesting both similar and disparate signs and symptoms. They shared a history of episodes of hypoglycemia and lactic acidosis, but had differing exam findings and developmental courses. Clinical acumen and exome sequencing combined with biochemical and functional studies identified three genetic conditions. One sibling had Smith-Magenis Syndrome and a nonsense mutation in the RAI1 gene. The second sibling had a de novo mutation in GRIN2B, which resulted in markedly reduced glutamate potency of the encoded receptor. Both siblings had a protein-destabilizing homozygous mutation in PCK1, which encodes the cytosolic isoform of phosphoenolpyruvate carboxykinase (PEPCK-C). In summary, we present the first clinically-characterized mutation of PCK1 and demonstrate that complex medical disorders can represent the co-occurrence of multiple diseases.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fosfoenolpiruvato Carboxiquinase (GTP)
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Fatores de Transcrição
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Receptores de N-Metil-D-Aspartato
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Fosfoenolpiruvato Carboxiquinase (ATP)
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Peptídeos e Proteínas de Sinalização Intracelular
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Síndrome de Smith-Magenis
Tipo de estudo:
Prognostic_studies
/
Risk_factors_studies
Limite:
Child
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Child, preschool
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Female
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Humans
Idioma:
En
Revista:
Mol Genet Metab
Assunto da revista:
BIOLOGIA MOLECULAR
/
BIOQUIMICA
/
METABOLISMO
Ano de publicação:
2014
Tipo de documento:
Article