Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Prader-Willi syndrome is a mental retardation genetic disorder also characterized by hypogonadism, hyperphagia and obesity. We report on a four-years-old boy, born to consanguineous parents, with uncommon co-occurrence of Prader-Willi syndrome, 47,XXY karyotype (Klinefelter syndrome) and coronal craniosynostosis. These are different unrelated conditions and it was not described before in the same patient to the best of our knowledge.
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PMID:Atypical presentation of Prader-Willi syndrome with Klinefelter (XXY karytype) and craniosynostosis. 1679 74

Prader-Willi syndrome is a complex multisystem disorder characterized by neonatal hypotonia, developmental delay, short stature, obesity, behaviour problems, hypothalamic hypogonadism and characteristic appearance. A number of sex chromosome abnormalities have been reported in children with Prader-Willi syndrome. We report on an infant with a 47, XXY karyotype and Prader-Willi syndrome diagnosed at 2 months of age. He is possibly the youngest to be reported with both Prader-Willi syndrome and Klinefelter syndrome. We have shown that the extra X chromosome causing Klinefelter syndrome is paternal in origin and Prader-Willi syndrome is due to maternal heterodisomy indicating that these two events occurred coincidentally.
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PMID:Prader-Willi and Klinefelter syndrome: a coincidence or not? 1735 60

Periventricular nodular heterotopia (PNH) is a rare neuronal migration disorder in which immature neurons fail to undergo a directed migration from the ventricular and subventricular zones to the cerebral cortex. Classic PNH occurs predominantly in females and is associated with periods of epilepsy and near-normal intelligence. One gene associated with PNH was mapped to chromosome Xq28. PNH with learning disability is reported in 15 male patients with several syndromes and various congenital abnormalities such as craniosynostosis, frontonasal malformation, and agenesis of the corpus callosum. We present a 26-year-old male patient who was followed up with the diagnosis of epilepsy from the age of 1 year. Additionally the patient had severe learning disability, obesity, and hypogonadism. Imaging of his brain demonstrated PNH. Klinefelter syndrome was clinically suspected, and analysis of his chromosomes revealed a karyotype 46,XY,der(19)t(X;19) (q11.1-11.2;p13.3). Molecular techniques, such as subtelomere-specific fluorescent in-situ hybridization and multicolour banding, were also used. The same translocation was demonstrated in his mother and his maternal grandmother. This family might help to explain the gene localization of X-linked recessive PNH. In our patient, PNH is associated with familial (X;19) translocation. To our knowledge, this unique combination has not been reported in the medical literature.
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PMID:Bilateral periventricular nodular heterotopia, severe learning disability, and epilepsy in a male patient with 46,XY,der(19)t(X;19) (q11.1-11.2;p13.3). 1735 80

Prader-Willi syndrome (PWS) is a well-defined syndrome of childhood-obesity which can serve as a model for investigating early onset childhood obesity. Many of the clinical features of PWS (e.g., hyperphagia, hypogonadotropic hypogonadism, growth hormone deficiency) are hypothesized to be due to abnormalities of the hypothalamus and/or pituitary gland. Children who become severely obese very early in life (i.e., before age 4 years) may also have a genetic etiology of their obesity, perhaps with associated neuroendocrine and hypothalamo-pituitary defects, as infants and very young children have limited access to environmental factors that contribute to obesity. We hypothesized that morphologic abnormalities of the pituitary gland would be seen in both individuals with PWS and other subjects with early onset morbid obesity (EMO). This case-control study included individuals with PWS (n = 27, age 3 months to 39 years), patients with EMO of unknown etiology (n = 16, age 4-22 years; defined as body mass index greater than the 97th centile for age before age 4 years), and normal weight siblings (n = 25, age 7 months to 43 years) from both groups. Participants had 3-dimensional magnetic resonance imaging to evaluate the pituitary gland, a complete history and physical examination, and measurement of basal pituitary hormones. Subjects with PWS and EMO had a higher prevalence of pituitary morphological abnormalities than did control subjects (74% PWS, 69% EMO, 8% controls; P < 0.001). Anterior pituitary hormone deficiencies were universal in individuals with PWS (low IGF-1 in 100%, P < 0.001 PWS vs. controls; central hypothyroidism in 19%, P = 0.052, and hypoplastic genitalia or hypogonadotropic hypogonadism in 100%, P < 0.001), and was often seen in individuals with EMO (6%, P = 0.89 vs. control, 31%, P = 0.002, and 25%, P = 0.018, respectively). The presence of a hypoplastic pituitary gland appeared to correlate with the presence of anterior pituitary hormone deficiencies in individuals with EMO, but no correlation was apparent in individuals with PWS. In conclusion, the high frequency of both morphological and hormonal abnormalities of the pituitary gland in both individuals with PWS and EMO suggests that abnormalities in the hypothalamo-pituitary axis are features not only of PWS, but also frequently of EMO of unknown etiology.
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PMID:Pituitary abnormalities in Prader-Willi syndrome and early onset morbid obesity. 1743 97

Small heterodimer partner (SHP; NR0B2) is an unusual orphan member of the nuclear receptor superfamily that functions as a corepressor of other nuclear receptors through heterodimeric interactions. Mutations in SHP are associated with mild obesity and insulin resistance. The protein domain structure of SHP is similar to Dosage-sensitive sex reversal adrenal hypoplasia congenita (AHC) critical region on the X chromosome, gene 1 (DAX1; NR0B1). Mutations in DAX1 cause AHC with associated hypogonadotropic hypogonadism. DAX1A is an alternatively spliced isoform of DAX1 that lacks the last 80 amino acids of the DAX1 C-terminal repressor domain and is replaced by a novel 10-amino acid motif. We have previously shown homodimerization of SHP and DAX1 individually, heterodimerization of DAX1 with SHP, and heterodimerization of DAX1 with DAX1A. In these studies, we investigated the domains and residues of SHP involved in SHP homodimerization and DAX1-SHP heterodimerization and also further characterized DAX1-DAX1 homodimerization and DAX1-DAX1A heterodimerization. We showed involvement of the SHP LXXLL motifs and AF-2 domain in SHP homodimerization and DAX1-SHP heterodimerization. We demonstrated redundancy of the LXXLL motifs in DAX1 homodimerization. While DAX1A subcellular localization is mostly cytoplasmic, DAX1-DAX1A heterodimers existed in the nucleus, suggesting differential functions for DAX1A in each compartment. We showed that the AF-2 domain of DAX1 is involved in DAX1-DAX1A heterodimerization. These results indicate that NR0B family members use similar mechanisms for homodimerization as well as heterodimerization. These resemble coactivator-receptor interactions that may have potential functional consequences for molecular mechanisms of the NR0B family.
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PMID:LXXLL motifs and AF-2 domain mediate SHP (NR0B2) homodimerization and DAX1 (NR0B1)-DAX1A heterodimerization. 1768 45

Obesity has recently become one of the most important public health problems. It is associated with a high rate of mortality, mainly because of cardiovascular disease, and can cause hormonal abnormalities such as hypogonadotropic hypogonadism. Weight loss is very beneficial for obese patients, because it results in improvement or even normalization of these conditions. In this report, we describe a morbidly obese patient with hypogonadotropic hypogonadism, which was probably caused by hyperprolactinemia and exacerbated by obesity-induced hormonal imbalances. After medical treatment for hyperprolactinemia and bariatric surgery, the patient's hormonal status became normal. Although morbid obesity can cause hypogonadotropic hypogonadism in men, the differential diagnosis should include other potential causes of hypogonadism if free testosterone levels are below normal.
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PMID:Hypogonadotropic hypogonadism in a patient with morbid obesity. 1795 51

Metabolic syndrome is characterized by insulin insensitivity, central obesity dyslipidemia, and hypertension. It is recognized as a risk factor for cardiovascular disease in men; by the time metabolic syndrome is diagnosed, however, most men already have entrenched cardiovascular disease. A reliable early warning sign is needed to alert physicians to those at risk for metabolic syndrome and cardiovascular disease. Low serum testosterone level has emerged as a reliable prognosticator of metabolic syndrome in men whose testosterone deficiency is genetic (Klinefelter syndrome), iatrogenic following surgery for testicular cancer, pharmacologically induced by gonadotropin-releasing hormone during prostate cancer treatment, or a natural consequence of aging. One third of men with type 2 diabetes mellitus are now recognized as testosterone deficient. Emerging evidence suggests that testosterone therapy may be able to reverse some aspects of metabolic syndrome.
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PMID:Testosterone, diabetes mellitus, and the metabolic syndrome. 1804 26

Prader-Willi syndrome (PWS [MIM 176270]) is a neurogenetic disorder characterized by decreased fetal activity, muscular hypotonia, failure to thrive, short stature, obesity, mental retardation, and hypogonadotropic hypogonadism. It is caused by the loss of function of one or more imprinted, paternally expressed genes on the proximal long arm of chromosome 15. Several potential PWS mouse models involving the orthologous region on chromosome 7C exist. Based on the analysis of deletions in the mouse and gene expression in PWS patients with chromosomal translocations, a critical region (PWScr) for neonatal lethality, failure to thrive, and growth retardation was narrowed to the locus containing a cluster of neuronally expressed MBII-85 small nucleolar RNA (snoRNA) genes. Here, we report the deletion of PWScr. Mice carrying the maternally inherited allele (PWScr(m-/p+)) are indistinguishable from wild-type littermates. All those with the paternally inherited allele (PWScr(m+/p-)) consistently display postnatal growth retardation, with about 15% postnatal lethality in C57BL/6, but not FVB/N crosses. This is the first example in a multicellular organism of genetic deletion of a C/D box snoRNA gene resulting in a pronounced phenotype.
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PMID:Deletion of the MBII-85 snoRNA gene cluster in mice results in postnatal growth retardation. 1816 85

Genetic variation in G protein-coupled receptors (GPCRs) results in the disruption of GPCR function in a wide variety of human genetic diseases. In vitro strategies have been used to elucidate the molecular pathologies that underlie naturally occurring GPCR mutations. Various degrees of inactive, overactive, or constitutively active receptors have been identified. These mutations often alter ligand binding, G protein coupling, receptor desensitization, and receptor recycling. The role of inactivating and activating calcium-sensing receptor (CASR) mutations is discussed with respect to familial hypocalciuric hypercalemia (FHH) and autosomal dominant hypocalemia (ADH). Among ADH mutations, those associated with tonic-clonic seizures are discussed. Other receptors discussed include rhodopsin, thyrotropin, parathyroid hormone, melanocortin, follicle-stimulating hormone, luteinizing hormone, gonadotropin-releasing hormone (GnRHR), adrenocorticotropic hormone, vasopressin, endothelin-beta, purinergic, and the G protein associated with asthma (GPRA). Diseases caused by mutations that disrupt GPCR function are significant because they might be selectively targeted by drugs that rescue altered receptors. Examples of drug development based on targeting GPCRs mutated in disease include the calcimimetics used to compensate for some CASR mutations, obesity therapeutics targeting melanocortin receptors, interventions that alter GnRHR loss from the cell surface in idiopathic hypogonadotropic hypogonadism and novel drugs that might rescue the P2RY12 receptor in a rare bleeding disorder. The discovery of GPRA suggests that drug screens against variant GPCRs may identify novel drugs. This review of the variety of GPCRs that are disrupted in monogenic disease provides the basis for examining the significance of common pharmacogenetic variants.
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PMID:G protein-coupled receptors disrupted in human genetic disease. 1837 Feb 33

The etiology of male breast cancer is largely unknown, reflecting its relative rarity. Although a number of previous studies have suggested relationships with a variety of medical conditions, the results have largely derived from case-control studies and may reflect recall biases. Within the large U.S. Veterans Affairs computerized medical care system database, we had the opportunity to access 26 million hospital discharge records over the period 1969-1996 and to relate various documented medical conditions to the risk of subsequent male breast cancer. This allowed us to calculate relative risks (RR) and 95% confidence intervals (CI) for male breast cancer associated with conditions occurring one or more years after initial hospitalization, adjusted for age, race, calendar year, duration of follow-up, and number of hospital visits. Among 4,501,578 men aged 18-100 years, a total of 642 cases of primary male breast cancer were identified (523 among whites, 119 among blacks). Medical conditions that were significantly related to risk were diabetes (RR 1.30, 95% CI 1.05-1.60), obesity (1.98, 1.55-2.54), orchitis/epididymitis (1.84, 1.10-3.08), Klinefelter syndrome (29.64, 12.26-71.68), and gynecomastia (5.86, 3.74-9.17). Additionally, among black patients, cholelithiasis emerged as a significant risk predictor (3.45, 1.59-7.47). Diseases that have previously been related to male breast cancer risk that were not supported by our study results included thyroid diseases, smoking-related conditions, liver cirrhosis, prostatic hyperplasia, and fractures. After adjustment for obesity, the association with diabetes disappeared, but that with gynecomastia persisted. In multivariate models that simultaneously considered all important medical predictors of risk, significant risks were seen for Klinefelter syndrome (16.83, 6.81-41.62), gynecomastia (5.08, 3.21-8.03), obesity (1.91, 1.50-2.44), and orchitis/epididymitis (1.80, 1.08-3.01). These results support previous speculations that male breast cancer is influenced not only by tissue at risk, but also by hormonal and inflammatory factors.
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PMID:Etiologic factors for male breast cancer in the U.S. Veterans Affairs medical care system database. 1933 May 25


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