Phenotypic manifestations associated with CAG-repeat expansion in the androgen receptor gene in male patients and heterozygous females: a clinical and molecular study of 30 families

Mariotti, Caterina; Castellotti, Barbara; Pareyson, Davide; Testa, D.; Eoli, Marica; Antozzi, Carlo; Silani, Vincenzo; Marconi, Roberto; Tezzon, Frediano; Siciliano, Gabriele; Marchini, C.; Gellera, Cinzia; Donato, Stefano Di

doi:10.1016/s0960-8966(99)00132-7

Cited by 115 publications

(123 citation statements)

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“…As clinical consequences, the number of CAGr was shown to be inversely associated with the risk of prostate cancer [27,28,31,32,33], benign prostatic hyperplasia [34,35], sperm production [36,37], bone density [38], endothelial function and HDL-cholesterol concentrations [39] as well as depression [40]. Furthermore, abnormal expansion of the CAGr length leads to Kennedy's disease, which is accompanied by morphological hypoandrogenic traits [41,42]. In this study we exploited this genetic determination of androgenicity to examine the causal contribution of testosterone to the regulation of body fat, leptin and insulin within a network of confounding variables, i.e.…”

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confidence: 99%

The CAG repeat polymorphism in the androgen receptor gene modulates body fat mass and serum concentrations of leptin and insulin in men

Zitzmann¹,

Gromoll²,

et al. 2003

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Aims/hypothesis. The relationship of androgens to the metabolic syndrome has not been resolved. The polymorphic number of CAG repeats within the androgen receptor gene is inversely associated with the transcriptional activity of target genes.This polymorphism might thus influence testosterone effects on body fat content and serum concentrations of leptin and insulin. The direct and indirect role of androgens within the metabolic syndrome should become clearer if this genetically determined effector is taken into account. Methods. The hypothesis was investigated in a crosssectional study involving 106 healthy 20-50 year old males. Results. Multiple regression models showed a positive independent correlation of the CAG repeat number with body fat content, leptin and insulin (partial r=0.39, 0.36 and 0.28, p<0.001, p<0.001 and p=0.006, respectively). Factor analysis yielded a five-dimensional model: two dimensions were influenced by the androgen receptor polymorphism, namely "body composition" which consisted of leptin, body fat mass, insulin, the number of CAG repeats (positive loadings) and physical activity (negative loading), and "lipid profile" which comprised low density lipoprotein cholesterol, cigarette smoking, triglycerides (positive loadings) as well as high density lipoprotein cholesterol and number of CAG repeats (negative loadings). Conclusions/interpretation. A low number of CAG repeats were independently associated with protective parameters (low body fat mass and plasma insulin) as well as with adverse parameters (low high density lipoprotein cholesterol concentrations). This suggests that the pivotal role of this polymorphism in modulating androgen effects on cardiovascular risk factors is of a complex nature and implies that its clinical impact, similar to that of androgens, is dependent on exogenous cofactors. [Diabetologia (2003) 46:31-39] Keywords Testosterone, body fat, leptin, insulin, androgen receptor, CAG repeat polymorphism. Corresponding author: E. Nieschlag, Institute of Reproductive Medicine of the University, Domagkstr. 11, 48129 Münster, Germany, E-mail: nieschl@uni-muenster.de Abbreviations: Ar, Adrogen Receptor; BFM, body fat mass; CAG, cytosin-adenin-guanin; CAGr, CAG repeats; FFM, fat free mass; HDL, high density lipoprotein; SHBG, sex hormone binding globuline; TBW, total body water; WHR, waist-to-hip ratio. Diabetologia (2003) 46:31-39 DOI 10.1007 The CAG repeat polymorphism in the androgen receptor gene modulates body fat mass and serum concentrations of leptin and insulin in men The term "metabolic syndrome" describes a pre-diabetic and pro-atherogenic state which is characterized by overweight, impaired glucose tolerance, hyperinsulinaemia, arterial hypertension, low concentrations of high density lipoprotein (HDL) cholesterol, hypertriglyceridaemia and disturbed haemostasis [1,2,3,4,5,6]. Several cross-sectional population studies found correlations between serum concentrations of testosterone and these cardiovascular risk factors, which, however, were opposi...

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The CAG repeat polymorphism in the androgen receptor gene modulates body fat mass and serum concentrations of leptin and insulin in men

Zitzmann¹,

Gromoll²,

et al. 2003

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“…It is an X-linked disease, whose genetic defect is an abnormal repeated expansion of the CAG trinucleotide at the first exon of the androgen receptor gene 1,2 .Individuals affected with KD have between 40-53 CAG repeats. Normal range is between 17-26 repeats 4 .…”

Section: Discussionmentioning

confidence: 99%

“…As well as that, they have distinct genetic mutations, allowing a correct diagnosis based on specific and precise laboratory testing 2,3 . We present a rare case of a patient with clinical features of Kennedy's disease, whose genetic testing was compatible with spinal muscle atrophy type III (Kugelberg-Welander's disease).…”

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confidence: 99%

Kennedy's disease phenotype with positive genetic study for Kugelberg-Welander's disease: case report

Trentin

Scola

Teive

et al. 2005

Arq. Neuro-Psiquiatr.

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We described a patient with clinical findings from Kennedy's disease and positive genetic study for Kugelberg-Welander's disease. A 24 years old man with negative family history presented with progressive spinal and bulbar muscular atrophy and gynecomastia at the age of 14. He was clinically diagnosed as having Kennedy's disease. However, a genetic study performed later was found to be negative for this disease and was positive for Kugelberg-Welander's disease, with deletion of the exons 7 and 8 in the "survival of motor neuron" gene.

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“…Some non-neural features, such as gynecomastia, can be fundamental in orientating the diagnostic process. The increase of creatine phosphokinase (CPK) levels may also be suggestive since it is found in almost all patients with levels that can be very high, until 38 fold the normal value, and decrease over time with the progression of the disease [10] [45]. Some endocrinal findings, for instance glucose intolerance or dyslipidemia, in association with lower motor neuron abnormalities, can support the diagnosis of SBMA.…”

Section: Diagnosis Of Sbmamentioning

confidence: 99%

“…More recently, because of high CPK serum levels [56] [57], which are higher than expected for a purely neurogenic disease, together with the presence of myogenic changes in muscle biopsy from patients, the hypothesis of a primary myopathic component contributing to the development of pathology has been put forward [46] [58] (Figure 3). Evidence of mixed neurogenic and myopathic processes has also been reported in mouse models of SBMA.…”

Section: Pathogenesismentioning

confidence: 99%

Kennedy disease (X-linked recessive bulbospinal neuronopathy): A comprehensive review from pathophysiology to therapy

2017

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Acknowledgments: the authors thank AFM-Téléthon, Téléthon Biobank, Institut pour la Recherche sur la Moelle épinière et l'Encéphale (IRME), Association pour la Recherche sur la SLA (ARSla) and the University of Padova for their research support.Kennedy disease (X-Linked recessive Bulbospinal Neuronopathy): a comprehensive review from pathophysiology to therapy. AbstractKennedy's disease, also known as spinal and bulbar muscular atrophy (SBMA), is a rare, adult-onset, Xlinked recessive neuromuscular disease. It is caused by expansion of a CAG repeat sequence in exon 1 of the androgen-receptor (AR) gene, encoding a poly-glutamine (polyQ) tract. Poly-Q-expanded AR accumulates in nuclei and initiates degeneration and loss of motor neurons and dorsal root ganglia. The disease has been retained to be a pure lower motor neuron disease for a long time, but recently the presence of important hyper-Creatine-Kinase-emia and of myopathic alterations on muscle biopsy has suggested the presence of a primary myopathy underlying a wide proportion of clinical manifestations. The disease, that affects male adults, is characterized by muscle weakness and atrophy localized proximally in the limbs and by bulbar involvement. Sensory disturbances are associated to the motor phenotype but may be subclinical. The most frequent systemic symptom is gynecomastia related to androgen insensitivity, but other abnormalities, such as heart rhythm and urinary disturbances, have also been reported. The course of the disease is slowly progressive with normal life expectancy. The diagnosis of SBMA is based on genetic testing, with 38 CAG repeats retained to be pathogenic. Even though several therapeutic attempts have been made in mouse models, no effective disease modifying therapy is available but symptomatic therapy is beneficial for the management of weakness, fatigability and bulbar symptoms.

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Phenotypic manifestations associated with CAG-repeat expansion in the androgen receptor gene in male patients and heterozygous females: a clinical and molecular study of 30 families

Cited by 115 publications

References 26 publications

The CAG repeat polymorphism in the androgen receptor gene modulates body fat mass and serum concentrations of leptin and insulin in men

The CAG repeat polymorphism in the androgen receptor gene modulates body fat mass and serum concentrations of leptin and insulin in men

Kennedy's disease phenotype with positive genetic study for Kugelberg-Welander's disease: case report

Kennedy disease (X-linked recessive bulbospinal neuronopathy): A comprehensive review from pathophysiology to therapy

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