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1.
Hum Mutat ; 39(10): 1416-1427, 2018 10.
Artículo en Inglés | MEDLINE | ID: mdl-29992659

RESUMEN

Here, we applied targeted capture to examine 153 genes representative of all the major vertebrate developmental pathways among 333 probands to rank their relative significance as causes for holoprosencephaly (HPE). We now show that comparisons of variant transmission versus nontransmission among 136 HPE Trios indicates some reported genes now lack confirmation, while novel genes are implicated. Furthermore, we demonstrate that variation of modest intrinsic effect can synergize with these driver mutations as gene modifiers.


Asunto(s)
Factores de Crecimiento de Fibroblastos/metabolismo , Predisposición Genética a la Enfermedad , Proteínas Hedgehog/metabolismo , Holoprosencefalia/genética , Holoprosencefalia/metabolismo , Transducción de Señal , Factor de Crecimiento Transformador beta/metabolismo , Factores de Crecimiento de Fibroblastos/genética , Frecuencia de los Genes , Estudios de Asociación Genética , Genotipo , Proteínas Hedgehog/genética , Holoprosencefalia/diagnóstico , Humanos , Patrón de Herencia , Mutación , Fenotipo , Síndrome , Factor de Crecimiento Transformador beta/genética
2.
Hum Mol Genet ; 25(10): 1912-1922, 2016 05 15.
Artículo en Inglés | MEDLINE | ID: mdl-26931467

RESUMEN

Mutations in FGFR1 have recently been associated with Hartsfield syndrome, a clinically distinct syndromic form of holoprosencephaly (HPE) with ectrodactly, which frequently includes combinations of craniofacial, limb and brain abnormalities not typical for classical HPE. Unrelated clinical conditions generally without craniofacial or multi-system malformations include Kallmann syndrome and idiopathic hypogonadotropic hypogonadism. FGFR1 is a principal cause for these less severe diseases as well. Here we demonstrate that of the nine FGFR1 mutations recently detected in our screen of over 200 HPE probands by next generation sequencing, only five distinct mutations in the kinase domain behave as dominant-negative mutations in zebrafish over-expression assays. Three FGFR1 mutations seen in HPE probands behave identical to wild-type FGFR1 in rescue assays, including one apparent de novo variation. Interestingly, in one HPE family, a deleterious FGFR1 allele was transmitted from one parent and a loss-of-function allele in FGF8 from the other parent to both affected daughters. This family is one of the clearest examples to date of gene:gene synergistic interactions causing HPE in humans.


Asunto(s)
Labio Leporino/genética , Fisura del Paladar/genética , Dedos/anomalías , Predisposición Genética a la Enfermedad , Deformidades Congénitas de la Mano/genética , Holoprosencefalia/genética , Hipogonadismo/genética , Discapacidad Intelectual/genética , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/genética , Alelos , Animales , Niño , Preescolar , Labio Leporino/fisiopatología , Fisura del Paladar/fisiopatología , Modelos Animales de Enfermedad , Femenino , Dedos/fisiopatología , Regulación de la Expresión Génica , Genotipo , Deformidades Congénitas de la Mano/fisiopatología , Secuenciación de Nucleótidos de Alto Rendimiento , Holoprosencefalia/fisiopatología , Humanos , Hipogonadismo/patología , Lactante , Discapacidad Intelectual/fisiopatología , Síndrome de Kallmann/genética , Síndrome de Kallmann/patología , Masculino , Mutación , Linaje , Índice de Severidad de la Enfermedad , Pez Cebra/genética
3.
PLoS One ; 8(2): e56913, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23468891

RESUMEN

This study was designed to determine the genotoxicity of a supraphysiological dose of triiodothyronine (T3) in both obese and calorie-restricted obese animals. Fifty male Wistar rats were randomly assigned to one of the two following groups: control (C; n = 10) and obese (OB; n = 40). The C group received standard food, whereas the OB group was fed a hypercaloric diet for 20 weeks. After this period, half of the OB animals (n = 20) were subjected to a 25%-calorie restriction of standard diet for 8 weeks forming thus a new group (OR), whereas the remaining OB animals were kept on the initial hypercaloric diet. During the following two weeks, 10 OR animals continued on the calorie restriction diet, whereas the remaining 10 rats of this group formed a new group (ORS) given a supraphysiological dose of T3 (25 µg/100 g body weight) along with the calorie restriction diet. Similarly, the remaining OB animals were divided into two groups, one that continued on the hypercaloric diet (OB, n = 10), and one that received the supraphysiological dose of T3 (25 µg/100 g body weight) along with the hypercaloric diet (OS, n = 10) for two weeks. The OB group showed weight gain, increased adiposity, insulin resistance, increased leptin levels and genotoxicity; T3 administration in OS animals led to an increase in genotoxicity and oxidative stress when compared with the OB group. The OR group showed weight loss and normalized levels of adiposity, insulin resistance, serum leptin and genotoxicity, thus having features similar to those of the C group. On the other hand, the ORS group, compared to OR animals, showed higher genotoxicity. Our results indicate that regardless of diet, a supraphysiological dose of T3 causes genotoxicity and potentiates oxidative stress.


Asunto(s)
Restricción Calórica , Hipertiroidismo/complicaciones , Obesidad/etiología , Triyodotironina/toxicidad , Tejido Adiposo , Animales , Composición Corporal , Peso Corporal , Ensayo Cometa , Ingestión de Energía , Resistencia a la Insulina , Leptina/sangre , Masculino , Malondialdehído/metabolismo , Ratas , Triyodotironina/administración & dosificación , Triyodotironina/sangre
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