Dihydropyrimidinase deficiency in four East Asian patients due to novel and rare DPYS mutations affecting protein structural integrity and catalytic activity.
Mol Genet Metab
; 122(4): 216-222, 2017 12.
Article
en En
| MEDLINE
| ID: mdl-29054612
ABSTRACT
Dihydropyrimidinase (DHP) is the second enzyme of the pyrimidine degradation pathway and catalyzes the ring opening of 5,6-dihydrouracil and 5,6-dihydrothymine. To date, only 31 genetically confirmed patients with a DHP deficiency have been reported and the clinical, biochemical and genetic spectrum of DHP deficient patients is, therefore, still largely unknown. Here, we show that 4 newly identified DHP deficient patients presented with strongly elevated levels of 5,6-dihydrouracil and 5,6-dihydrothymine in urine and a highly variable clinical presentation, ranging from asymptomatic to infantile spasm and reduced white matter and brain atrophy. Analysis of the DHP gene (DPYS) showed the presence of 8 variants including 4 novel/rare missense variants and one novel deletion. Functional analysis of recombinantly expressed DHP mutants carrying the p.M250I, p.H295R, p.Q334R, p.T418I and the p.R490H variant showed residual DHP activities of 2.0%, 9.8%, 9.7%, 64% and 0.3%, respectively. The crystal structure of human DHP indicated that all point mutations were likely to cause rearrangements of loops shaping the active site, primarily affecting substrate binding and stability of the enzyme. The observation that the identified mutations were more prevalent in East Asians and the Japanese population indicates that DHP deficiency may be more common than anticipated in these ethnic groups.
Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Mutación Puntual
/
Pueblo Asiatico
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Amidohidrolasas
/
Errores Innatos del Metabolismo
Tipo de estudio:
Prognostic_studies
Límite:
Child
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Child, preschool
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Female
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Humans
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Infant
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Male
País/Región como asunto:
Asia
Idioma:
En
Revista:
Mol Genet Metab
Asunto de la revista:
BIOLOGIA MOLECULAR
/
BIOQUIMICA
/
METABOLISMO
Año:
2017
Tipo del documento:
Article
País de afiliación:
Países Bajos