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1.
J Pharmacol Exp Ther ; 316(1): 431-9, 2006 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-16203827

RESUMEN

To elucidate the role of endogenous ghrelin in the regulation of energy homeostasis and gastric emptying, ghrelin knockout mice (ghrelin(-/-)) were generated. Body weight, food intake, respiratory quotient, and heat production (indirect calorimetry), and gastric emptying ((14)C breath test) were compared between ghrelin(+/+) and ghrelin(-/-) mice. In both strains, the effect of exogenous ghrelin on gastric emptying and food intake was determined. Ghrelin(-/-) mice showed some subtle phenotypic changes. Body weight gain and 24-h food intake were not affected, but interruption of the normal light/dark cycle triggered additional food intake in old ghrelin(+/+) but not in ghrelin(-/-) mice. Exogenous ghrelin increased food intake in both genotypes with a bell-shaped dose-response curve that was shifted to the left in ghrelin(-/-) mice. During the dark period, young ghrelin(-/-) mice had a lower respiratory quotient, whereas their heat production was higher than that of the wild-type littermates, inferring a leaner body composition of the ghrelin(-/-) mice. Absence of ghrelin did not affect gastric emptying, and the bell-shaped dose-response curves of the acceleration of gastric emptying by exogenous ghrelin were not shifted between both strains. In conclusion, ghrelin is not an essential regulator of food intake and gastric emptying, but its loss may be compensated by other redundant inputs. In old mice, meal initiation triggered by the light/dark cue may be related to ghrelin. In young animals, ghrelin seems to be involved in the selection of energy stores and in the partitioning of metabolizable energy between storage and dissipation as heat.


Asunto(s)
Metabolismo Energético/genética , Vaciamiento Gástrico/genética , Homeostasis/genética , Hormonas Peptídicas/genética , Hormonas Peptídicas/fisiología , Envejecimiento/fisiología , Animales , Regulación de la Temperatura Corporal/genética , Regulación de la Temperatura Corporal/fisiología , Peso Corporal/genética , Peso Corporal/fisiología , Pruebas Respiratorias , Rastreo Diferencial de Calorimetría , Caprilatos , Ingestión de Alimentos/efectos de los fármacos , Ingestión de Alimentos/genética , Ingestión de Alimentos/fisiología , Metabolismo Energético/fisiología , Vaciamiento Gástrico/fisiología , Motilidad Gastrointestinal/genética , Motilidad Gastrointestinal/fisiología , Ghrelina , Homeostasis/fisiología , Inmunohistoquímica , Ratones , Ratones Noqueados , Consumo de Oxígeno/genética , Consumo de Oxígeno/fisiología , Hormonas Peptídicas/farmacología , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Ghrelina
2.
J Med Genet ; 41(3): 147-54, 2004 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-14985372

RESUMEN

INTRODUCTION: Mutations in GJB2 are the most common cause of non-syndromic autosomal recessive hearing impairment, ranging from mild to profound. Mutation analysis of this gene is widely available as a genetic diagnostic test. OBJECTIVE: To assess a possible genotype-phenotype correlation for GJB2. DESIGN: Retrospective analysis of audiometric data from people with hearing impairment, segregating two GJB2 mutations. SUBJECTS: Two hundred and seventy seven unrelated patients with hearing impairment who were seen at the ENT departments of local and university hospitals from Italy, Belgium, Spain, and the United States, and who harboured bi-allelic GJB2 mutations. RESULTS: We found that 35delG homozygotes have significantly more hearing impairment, compared with 35delG/non-35delG compound heterozygotes. People with two non-35delG mutations have even less hearing impairment. We observed a similar gradient of hearing impairment when we categorised mutations as inactivating (that is, stop mutations or frame shifts) or non-inactivating (that is, missense mutations). We demonstrated that certain mutation combinations (including the combination of 35delG with the missense mutations L90P, V37I, or the splice-site mutation IVS1+1G>A, and the V37I/V37I genotype) are associated with significantly less hearing impairment compared with 35delG homozygous genotypes. CONCLUSIONS: This study is the first large systematic analysis indicating that the GJB2 genotype has a major impact on the degree of hearing impairment, and identifying mild genotypes. Furthermore, this study shows that it will be possible to refine this correlation and extend it to additional genotypes. These data will be useful in evaluating habilitation options for people with GJB2 related deafness.


Asunto(s)
Conexinas/genética , Pérdida Auditiva/genética , Pérdida Auditiva/fisiopatología , Mutación/genética , Adolescente , Adulto , Edad de Inicio , Anciano , Envejecimiento , Alelos , Audiometría , Bélgica , Niño , Preescolar , Conexina 26 , Análisis Mutacional de ADN , Progresión de la Enfermedad , Pruebas Genéticas , Genotipo , Pérdida Auditiva/clasificación , Humanos , Lactante , Italia , Persona de Mediana Edad , Fenotipo , Estudios Retrospectivos , España , Estados Unidos
3.
Ned Tijdschr Geneeskd ; 147(44): 2170-2, 2003 Nov 01.
Artículo en Holandés | MEDLINE | ID: mdl-14626834

RESUMEN

DFNA6/-14 is a nonsyndromic, autosomal dominant form of hearing impairment that is characterised by low-frequency sensorineural hearing loss, which in some cases is progressive. It is the only known form of dominantly inherited low-frequency hearing impairment in the Netherlands. It is caused by heterozygous non-inactivating mutations in the WFSI gene, which are also present in the Wolfram or DIDMOAD syndrome.


Asunto(s)
Pérdida Auditiva Sensorineural/genética , Proteínas de la Membrana/genética , Mutación , Audiometría , Progresión de la Enfermedad , Humanos , Familia de Multigenes , Linaje
4.
Hum Mol Genet ; 10(22): 2501-8, 2001 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-11709537

RESUMEN

Non-syndromic low frequency sensorineural hearing loss (LFSNHL) affecting only 2000 Hz and below is an unusual type of hearing loss that worsens over time without progressing to profound deafness. This type of LFSNHL may be associated with mild tinnitus but is not associated with vertigo. We have previously reported two families with autosomal dominant LFSNHL linked to adjacent but non-overlapping loci on 4p16, DFNA6 and DFNA14. However, further study revealed that an individual with LFSNHL in the DFNA6 family who had a recombination event that excluded the DFNA14 candidate region was actually a phenocopy, and consequently, DFNA6 and DFNA14 are allelic. LFSNHL appears to be genetically nearly homogeneous, as only one LFSNHL family is known to map to a different chromosome (DFNA1). The DFNA6/14 critical region includes WFS1, the gene responsible for Wolfram syndrome, an autosomal recessive disorder characterized by diabetes mellitus and optic atrophy, and often, deafness. Herein we report five different heterozygous missense mutations (T699M, A716T, V779M, L829P, G831D) in the WFS1 gene found in six LFSNHL families. Mutations in WFS1 were identified in all LFSNHL families tested, with A716T arising independently in two families. None of the mutations was found in at least 220 control chromosomes with the exception of V779M, which was identified in 1/336 controls. This frequency is consistent with the prevalence of heterozygous carriers for Wolfram syndrome estimated at 0.3-1%. An increased risk of sensorineural hearing loss has been reported in such carriers. Therefore, we conclude that mutations in WFS1 are a common cause of LFSNHL.


Asunto(s)
Pérdida Auditiva Sensorineural/genética , Proteínas de la Membrana/genética , Alelos , Umbral Auditivo , Secuencia de Bases , Cromosomas Humanos Par 4/genética , ADN/química , ADN/genética , Análisis Mutacional de ADN , Salud de la Familia , Femenino , Frecuencia de los Genes , Haplotipos , Pérdida Auditiva Sensorineural/patología , Humanos , Masculino , Repeticiones de Microsatélite , Mutación , Mutación Missense , Linaje , Polimorfismo de Nucleótido Simple , Polimorfismo Conformacional Retorcido-Simple
5.
Anat Rec ; 259(2): 229-36, 2000 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-10820324

RESUMEN

A newly developed desktop microtomograph was used to evaluate whether it is suitable for visualizing the three-dimensional (3D) morphology of the mouse inner ear (at a micrometer level) and whether it is applicable as a fast screening tool to detect hereditary abnormalities in this organ. To this end, the epistatic circler, a mutant mouse showing abnormal circling behaviour, was used as a model. The inner ears were dissected out, formaldehyde-fixed, and scanned at maximal resolution along the longitudinal axis. After segmentation, stacks of tomographic images were used for 3D reconstruction of the bony labyrinth. Finally, the obtained data were correlated with subsequent conventional histological examination. The spatial resolution (8 microm) achieved by this instrument, was found to be far superior to that obtained by conventional computer tomography (CT) and magnetic resonance (MR)-imaging equipment. The technique provides detailed tomographic images of the bony labyrinths and enables an adequate 3D reconstruction of the inner ear structures in this small mammal. In addition, it allows a screening for pathologic specimens prior to the more time- and labour-consuming histological techniques, which are still essential to gather information at a (sub)cellular level. This imaging technique can be regarded as a valuable tool in future research on hereditary inner ear abnormalities.


Asunto(s)
Oído Interno/anatomía & histología , Tomografía Computarizada por Rayos X/instrumentación , Animales , Oído Interno/anomalías , Oído Interno/diagnóstico por imagen , Epistasis Genética , Imagen por Resonancia Magnética , Ratones , Ratones Endogámicos C57BL , Ratones Mutantes , Programas Informáticos , Tomografía Computarizada por Rayos X/métodos
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