RESUMEN

Considerable attention has been paid to the role of sex steroids during periods of major skeletal turnover, but the interaction of the gonadotropic hormones, which include LH, FSH, and human chorionic gonadotropin (hCG), within bone tissue have been overlooked. The question is pertinent due to the recent detection of extragonadal expression of gonadotropin receptors. Western blotting, immunolocalization, and RT-PCR supported the presence of osteoblast LH receptors. However, osteoblast cells failed to bind [(125)I]hCG and treatment with hCG failed to generate either cAMP or phosphorylated ERK 1/2. Bone mineral density (BMD) and bone histomorphometry were examined in the following models: 1) LH receptor null mutant (LuRKO) mice; 2) transgenic mice overexpressing hCG (hCG alphabeta+); and 3) ovariectomized (OVX) hCG alphabeta+ model. Male LuRKO mice showed a decrease in BMD after 5 months, apparently secondary to suppressed gonadal steroid production. Similarly, 9- to 10-wk-old female LuRKO mice exhibited decreases in histomorphometric parameters tested. The data indicate that loss of LH signaling results in a reduction in bone formation or an increase in bone resorption. By contrast, there were significant increases in BMD and histomorphometric indices for female, but not male, hCG alphabeta+ mice, indicating that chronic exposure to hCG results in bone formation or a decrease in bone resorption. However, OVX of the hCG alphabeta+ mice resulted in a significant reduction in BMD comparable to OVX WT controls. Although gonadotropin levels are tightly linked to sex steroid titers, it appears that their effects on the skeleton are indirect.

Asunto(s)

Huesos/fisiología , Gonadotropina Coriónica/genética , Fenotipo , Receptores de HL/deficiencia , Adulto , Animales , Densidad Ósea/fisiología , Línea Celular , Células Cultivadas , Gonadotropina Coriónica/farmacología , Gonadotropina Coriónica/fisiología , AMP Cíclico/biosíntesis , Femenino , Humanos , Tumor de Células de Leydig , Hormona Luteinizante/metabolismo , Masculino , Ratones , Ratones Transgénicos , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Osteoblastos/química , Osteoblastos/efectos de los fármacos , Osteoblastos/metabolismo , Ovariectomía , Ovario/química , Fosforilación , ARN Mensajero/análisis , Ratas , Receptores de HL/análisis , Receptores de HL/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Células Tumorales Cultivadas

RESUMEN

Mutations of the luteinizing hormone (LH) subunit genes are extremely rare. Only one polymorphic LHbeta gene variant makes an exception. In 1992, an immunologically anomalous form of LH was found in a healthy woman, and it was subsequently found to be caused by two point mutations leading to two amino acid substitutions in the LHbeta subunit. Of the two point mutations, Trp(8)Arg and Ile(15)Thr, the first one is mainly responsible for the altered immunoreactivity and the latter one introduces an extra glycosylation site into Asn(13) of the mutated LHbeta peptide. The frequency of this variant LHbeta allele differs widely between ethnic groups, being most common in aboriginal Australians (carrier frequency >50%; allelic frequency 28.3%) and totally lacking from Kotas of Southern India. Functional differences have been detected when wild-type LH and variant LH have been compared. Variant LH possesses increased in vitro bioactivity, whereas its half-life in circulation is shorter in comparison to wild-type LH. Also the regulation of the variant LHbeta gene differs due to additional changes in its promoter sequence. Correlations of occurrence of variant LH with various clinical conditions involving LH function suggest that it represents a biologically less active form of LH and may be related to borderline suppression of gonadal function, including subfertility. In this article, we will review the current information about the differences observed in structure and functions between the wild-type and variant LH, as well as their possible pathophysiological correlations.

Asunto(s)

Frecuencia de los Genes/genética , Gónadas/fisiología , Hormona Luteinizante/genética , Hipófisis/fisiología , Síndrome del Ovario Poliquístico/genética , Receptores de HL/fisiología , Animales , Exones/genética , Femenino , Hormonas Glicoproteicas de Subunidad alfa/genética , Humanos , Masculino , Mutación Missense/genética , Obesidad/genética , Mutación Puntual/genética , Polimorfismo Genético/genética

RESUMEN

The mitochondrial DNA (mtDNA) sequence variation of 24 Finnish Leber hereditary optic neuroretinopathy (LHON) probands was characterized by sequencing and restriction endonuclease analyses. All LHON-associated substitutions and Caucasoid haplogroup-specific mutations were screened in the families. Analysis of the mtDNAs revealed that the Finnish LHON families have two unique features: an absence of the ND6/14484 mutation and a high number of families (10/24) without the primary mutations ND1/3460 and ND4/11778. Furthermore, the LHON families showed considerable mtDNA heterogeneity: among 24 families 22 haplotypes were detected. Overall, the haplogrouping of LHON families was similar to other European populations. However, the frequency of ND4/11778-positive families in haplogroup J was high, which may indicate that background mutations in this haplogroup together with the ND4/11778 primary mutation promote the penetrance of LHON.

Asunto(s)

ADN Mitocondrial/genética , Haplotipos , Atrofias Ópticas Hereditarias/genética , Filogenia , Adolescente , Adulto , Niño , Femenino , Finlandia , Heterogeneidad Genética , Variación Genética/genética , Humanos , Masculino , Persona de Mediana Edad , Atrofias Ópticas Hereditarias/fisiopatología , Linaje , Polimorfismo de Longitud del Fragmento de Restricción , Población Blanca/genética

RESUMEN

A lowered efficiency of oxidative phosphorylation was recently found in a Leber hereditary optic neuropathy (LHON) proband carrying a mutation in the mtDNA gene for subunit 6 of the membrane-bound F0 segment of the F1F0-ATP synthase [9]. This phenotype was transferred to cytoplasmic hybrid cells together with the mutation, proving its functional significance. Increasing the respiratory rate in the mitochondria from this mutant raised the ATP/2e- ratio back to normal values. A different mutation in the same mtDNA gene has been found in patients with the NARP syndrome [10]. Although the ATP/2e- ratio is also decreased in this mutant, in this case an increase in the respiratory rate could not compensate for it. Whilst both mutations affect subunit 6 of the proton-translocating F0 segment, the LHON mutation induces a proton leak whereas the NARP mutation blocks proton translocation. Hence, the latter will have much more destructive metabolic consequences in agreement with the large clinical differences between the two diseases.

Asunto(s)

Mutación , Atrofias Ópticas Hereditarias/genética , ATPasas de Translocación de Protón/genética , Adenosina Trifosfato/biosíntesis , ADN Mitocondrial , Humanos , Cinética , Fosforilación Oxidativa , ATPasas de Translocación de Protón/metabolismo , Síndrome

RESUMEN

Leber hereditary optic neuropathy (LHON) is a maternally inherited eye disease most commonly caused by mitochondrial DNA (mtDNA) point mutation at position 11778, 3460, or 14484. Approximately 14% of families show heteroplasmy for the pathogenic mutations but little is known about the mutational burden in different tissues of these heteroplasmic individuals. Consequently, estimating the risks of visual loss is difficult. This study presents quantitative mutation analyses of tissues representing all embryonal layers in two families heteroplasmic for the 11778 mutation. These analyses show that a high amount of mutated mtDNA in leukocytes is correlated with a high proportion of mutated mtDNA in other tissues.

Asunto(s)

Mutación , Atrofias Ópticas Hereditarias/genética , ADN Mitocondrial , Femenino , Humanos , Masculino , Linaje

RESUMEN

BACKGROUND: Leber hereditary optic neuropathy (LHON) is associated with primary and secondary mutations in mitochondrial DNA. Clinical studies suggest that there is a wide spectrum of clinical expression. METHODS: Fifty-three affected and 131 unaffected maternal relatives from 21 pedigrees with LHON were studied neuro-ophthalmologically and followed over a period of 14 years. Mitochondrial DNA analysis was performed on their blood specimens. RESULTS: Thirty-two affected (60%) individuals from ten families harbored the 11778 mutation and ten individuals (19%) from three families harbored the 3460 mutation. No confirmed primary mutation was detected in 11 (21%) affected individuals from eight families. The visual outcome was better in families with the 3460 mutation than in those with the 11778 mutation. Secondary mutations did not affect the penetrance or the visual outcome. Fifteen patients had a favorable outcome; seven of whom had subclinical disease, two had slowly progressive LHON with a favorable visual outcome, and six had classic LHON with spontaneous recovery. In seven patients, the onset of the disease had been in childhood. These patients had a more favorable prognosis than the adults. Results of eye examinations of asymptomatic maternal relatives showed subclinically affected individuals. CONCLUSIONS: In addition to classic LHON, the disease can manifest itself in three different atypical forms: subclinical disease, slowly progressive LHON with a favorable visual outcome, and LHON with the classic acute stage but spontaneous visual recovery. The current study suggests that the ophthalmologic findings and outcome in LHON are independent of secondary mutations.

Asunto(s)

ADN Mitocondrial/genética , Atrofias Ópticas Hereditarias/genética , Atrofias Ópticas Hereditarias/patología , Nervio Óptico/patología , Mutación Puntual , Adolescente , Adulto , Edad de Inicio , Niño , Percepción de Color , ADN/análisis , Femenino , Fondo de Ojo , Humanos , Masculino , Persona de Mediana Edad , Linaje , Agudeza Visual , Campos Visuales

RESUMEN

Previous studies suggest that Leber's hereditary optic neuropathy (LHON) may be a systemic disorder with manifestations in organs other than the optic nerves. To evaluate nervous system involvement 38 men and eight women with LHON were re-examined. The patients were divided into three groups according to mtDNA analysis--namely, patients with the 11778 or with the 3460 mutation and patients without these primary mutations. Fifty nine per cent of patients had neurological abnormalities but there was no significant difference between the three groups. Movement disorders were the most common finding; nine patients had constant postural tremor, one chronic motor tic disorder, and one parkinsonism with dystonia. Four patients had peripheral neuropathy with no other evident cause. Two patients had a multiple sclerosis-like syndrome; in both patients MRI showed changes in the periventricular white matter. Thoracic kyphosis occurred in seven patients, five of whom had the 3460 mutation. In one patient the 3460 mutation was associated with involvement of the brain stem. It is suggested that various movement disorders, multiple sclerosis-like illness, and deformities of the vertebral column may associate pathogenetically with LHON.

Asunto(s)

Enfermedades del Sistema Nervioso/complicaciones , Atrofias Ópticas Hereditarias/genética , Adulto , Encéfalo/patología , Femenino , Finlandia , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Mutación , Atrofias Ópticas Hereditarias/complicaciones

Asunto(s)

Mitocondrias/genética , Mutación , Atrofias Ópticas Hereditarias/genética , Fosforilación Oxidativa , ATPasas de Translocación de Protón/genética , Adulto , Anciano , ADN Mitocondrial/genética , ADN Mitocondrial/metabolismo , Desoxirribonucleasas de Localización Especificada Tipo II/metabolismo , Femenino , Finlandia/epidemiología , Humanos , Masculino , Mitocondrias/enzimología , Atrofias Ópticas Hereditarias/enzimología , Atrofias Ópticas Hereditarias/epidemiología , Linaje , Reacción en Cadena de la Polimerasa

RESUMEN

The mitochondrial complex I genes were sequenced in seven Leber hereditary optic neuroretinopathy (LHON) families without the ND4/11,778 and ND1/3460 mutations. Four replacement mutations restricted only to LHON families were found, one in the ND1 gene at nt 4025, and three in the ND5 gene at nt 12,811, 13,637, and 13,967. The mutations did not change evolutionarily conserved amino acids suggesting that they are not primary LHON mutations in these families. They may be considered as secondary LHON mutations serving as exacerbating factors in an appropriate genetic background. A complex III mutation, cyt b/15,257, has been suggested to be one of the primary mutations causing LHON. Its presence was determined for 23 Finnish LHON families, and it was detected in two families harboring the ND4/11,778 mutation. Similarly, complex IV mutation COI/7444 was screened in Finnish LHON families, and it was found in one family carrying the ND1/3460 mutation.

Asunto(s)

ADN Mitocondrial , Mutación , Atrofias Ópticas Hereditarias/genética , Aminoácidos/genética , Secuencia de Bases , ADN/análisis , Análisis Mutacional de ADN , Humanos , Reacción en Cadena de la Polimerasa , Polimorfismo Genético , Polimorfismo de Longitud del Fragmento de Restricción