Congenital hypogonadotropic hypogonadism (CHH) and its anosmia-associated form (Kallmann syndrome KS) are genetically heterogeneous. Among the >15 genes implicated in these conditions, mutations in ...FGF8 and FGFR1 account for ∼12% of cases; notably, KAL1 and HS6ST1 are also involved in FGFR1 signaling and can be mutated in CHH. We therefore hypothesized that mutations in genes encoding a broader range of modulators of the FGFR1 pathway might contribute to the genetics of CHH as causal or modifier mutations. Thus, we aimed to (1) investigate whether CHH individuals harbor mutations in members of the so-called “FGF8 synexpression” group and (2) validate the ability of a bioinformatics algorithm on the basis of protein-protein interactome data (interactome-based affiliation scoring IBAS) to identify high-quality candidate genes. On the basis of sequence homology, expression, and structural and functional data, seven genes were selected and sequenced in 386 unrelated CHH individuals and 155 controls. Except for FGF18 and SPRY2, all other genes were found to be mutated in CHH individuals: FGF17 (n = 3 individuals), IL17RD (n = 8), DUSP6 (n = 5), SPRY4 (n = 14), and FLRT3 (n = 3). Independently, IBAS predicted FGF17 and IL17RD as the two top candidates in the entire proteome on the basis of a statistical test of their protein-protein interaction patterns to proteins known to be altered in CHH. Most of the FGF17 and IL17RD mutations altered protein function in vitro. IL17RD mutations were found only in KS individuals and were strongly linked to hearing loss (6/8 individuals). Mutations in genes encoding components of the FGF pathway are associated with complex modes of CHH inheritance and act primarily as contributors to an oligogenic genetic architecture underlying CHH.
Between the genetic extremes of rare monogenic and common polygenic diseases lie diverse oligogenic disorders involving mutations in more than one locus in each affected individual. Elucidating the ...principles of oligogenic inheritance and mechanisms of genetic interactions could help unravel the newly appreciated role of rare sequence variants in polygenic disorders. With few exceptions, however, the precise genetic architecture of oligogenic diseases remains unknown. Isolated gonadotropin-releasing hormone (GnRH) deficiency caused by defective secretion or action of hypothalamic GnRH is a rare genetic disease that manifests as sexual immaturity and infertility. Recent reports of patients who harbor pathogenic rare variants in more than one gene have challenged the long-held view that the disorder is strictly monogenic, yet the frequency and extent of oligogenicity in isolated GnRH deficiency have not been investigated. By systematically defining genetic variants in large cohorts of well-phenotyped patients (n = 397), family members, and unaffected subjects (n = 179) for the majority of known disease genes, this study suggests a significant role of oligogenicity in this disease. Remarkably, oligogenicity in isolated GnRH deficiency was as frequent as homozygosity/compound heterozygosity at a single locus (2.5%). Among the 22% of patients with detectable rare protein-altering variants, the likelihood of oligogenicity was 11.3%. No oligogenicity was detected among controls (P < 0.05), even though deleterious variants were present. Viewing isolated GnRH deficiency as an oligogenic condition has implications for understanding the pathogenesis of its reproductive and nonreproductive phenotypes; deciphering the etiology of common GnRH-related disorders; and modeling the genetic architecture of other oligogenic and multifactorial diseases.
Cross-sectional studies are likely to underestimate age-related changes in skeletal muscle strength and mass. The purpose of this longitudinal study was to assess whole muscle and single muscle fiber ...alterations in the same cohort of 12 older (mean age: start of study 71.1+/-5.4 yr and end of study 80+/-5.3 yr) volunteers (5 men) evaluated 8.9 yr apart. No significant changes were noted at follow-up in body weight, body mass index, and physical activity. Muscle strength, evaluated using isokinetic dynamometry, and whole muscle specific force of the knee extensors were significantly lower at follow-up. This was accompanied by a significant reduction (5.7%) in cross-sectional area of the total anterior muscle compartment of the thigh as evaluated by computed tomography. Muscle histochemistry showed no significant changes in fiber type distribution or fiber area. Experiments with chemically skinned single muscle fibers (n=411) demonstrated no change in type I fiber size but an increase in IIA fiber diameter. A trend toward an increase in maximal force in both fiber types was observed. Maximum unloaded shortening velocity did not change. In conclusion, single muscle fiber contractile function may be preserved in older humans in the presence of significant alterations at the whole muscle level. This suggests that surviving fibers compensate to partially correct muscle size deficits in an attempt to maintain optimal force-generating capacity.
THE SINS OF THE FATHER Hughes, Virginia
Nature (London),
03/2014, Letnik:
507, Številka:
7490
Journal Article
Recenzirano
Where one's ancestors lived, or how much they valued education, can clearly have effects that pass down through the generations. But what about the legacy of their health: whether they smoked, ...endured famine or fought in a war?
Reversal of idiopathic hypogonadotropic hypogonadism Raivio, Taneli; Falardeau, John; Dwyer, Andrew ...
New England journal of medicine/The New England journal of medicine,
08/2007, Letnik:
357, Številka:
9
Journal Article
Recenzirano
Odprti dostop
Idiopathic hypogonadotropic hypogonadism, which may be associated with anosmia (the Kallmann syndrome) or with a normal sense of smell, is a treatable form of male infertility caused by a congenital ...defect in the secretion or action of gonadotropin-releasing hormone (GnRH). Patients have absent or incomplete sexual maturation by the age of 18. Idiopathic hypogonadotropic hypogonadism was previously thought to require lifelong therapy. We describe 15 men in whom reversal of idiopathic hypogonadotropic hypogonadism was sustained after discontinuation of hormonal therapy.
We defined the sustained reversal of idiopathic hypogonadotropic hypogonadism as the presence of normal adult testosterone levels after hormonal therapy was discontinued.
Ten sustained reversals were identified retrospectively. Five sustained reversals were identified prospectively among 50 men with idiopathic hypogonadotropic hypogonadism after a mean (+/-SD) duration of treatment interruption of 6+/-3 weeks. Of the 15 men who had a sustained reversal, 4 had anosmia. At initial evaluation, 6 men had absent puberty, 9 had partial puberty, and all had abnormal secretion of GnRH-induced luteinizing hormone. All 15 men had received previous hormonal therapy to induce virilization, fertility, or both. Among those whose hypogonadism was reversed, the mean serum level of endogenous testosterone increased from 55+/-29 ng per deciliter (1.9+/-1.0 nmol per liter) to 386+/-91 ng per deciliter (13.4+/-3.2 nmol per liter, P<0.001), the luteinizing hormone level increased from 2.7+/-2.0 to 8.5+/-4.6 IU per liter (P<0.001), the level of follicle-stimulating hormone increased from 2.5+/-1.7 to 9.5+/-12.2 IU per liter (P<0.01), and testicular volume increased from 8+/-5 to 16+/-7 ml (P<0.001). Pulsatile luteinizing hormone secretion and spermatogenesis were documented.
Sustained reversal of normosmic idiopathic hypogonadotropic hypogonadism and the Kallmann syndrome was noted after discontinuation of treatment in about 10% of patients with either absent or partial puberty. Therefore, brief discontinuation of hormonal therapy to assess reversibility of hypogonadotropic hypogonadism is reasonable. (ClinicalTrials.gov number, NCT00392756 ClinicalTrials.gov.).
Background: Estimates of body-composition change in older adults are mostly derived from cross-sectional data. Objective: We examined the natural longitudinal patterns of change in fat-free mass ...(FFM) and fat mass (FM) in older adults and explored the effect of physical activity, weight change, and age on these changes. Design: The body composition measured by hydrodensitometry and the level of sports and recreational activity (SRA) of 53 men and 78 women with a mean (+/-SD) initial age of 60.7 +/- 7.8 y were examined on 2 occasions separated by a mean (+/-SD) time of 9.4 +/- 1.4 y. Results: FFM decreased in men (2.0% per decade) but not in women, whereas FM increased similarly in both sexes (7.5% per decade). Levels of SRA decreased more in men than in women over the follow-up period. Baseline age and level of SRA were inversely and independently associated with changes in FM in women only. Neither age nor level of SRA was associated with changes in FFM in men or women. Weight-stable subjects lost FFM. FFM accounted for 19% of body weight in those who gained weight, even in the presence of decreased levels of SRA. Loss of FFM (33% of body weight) was pronounced in those who lost weight, despite median SRA levels >4184 kJ/wk. Conclusions: On average, FM increased; however, the increase in women was attenuated with advancing age. The decrease in FFM over the follow-up period was small and masked the wide interindividual variation that was dependent on the magnitude of weight change. The contribution of weight stability, modest weight gains, or lifestyle changes that include regular resistance exercise in attenuating lean-tissue loss with age should be explored.
Context: Mutations in TAC3 and TACR3 (encoding neurokinin B and its receptor) have been identified in Turkish patients with idiopathic hypogonadotropic hypogonadism (IHH), but broader populations ...have not yet been tested and genotype-phenotype correlations have not been established.
Objective: A broad cohort of normosmic IHH probands was screened for mutations in TAC3/TACR3 to evaluate the prevalence of such mutations and define the genotype/phenotype relationships.
Design and Setting: The study consisted of sequencing of TAC3/TACR3, in vitro functional assays, and neuroendocrine phenotyping conducted in tertiary care centers worldwide.
Patients or Other Participants: 345 probands, 18 family members, and 292 controls were studied.
Intervention: Reproductive phenotypes throughout reproductive life and before and after therapy were examined.
Main Outcome Measure: Rare sequence variants in TAC3/TACR3 were detected.
Results: In TACR3, 19 probands harbored 13 distinct coding sequence rare nucleotide variants three nonsense mutations, six nonsynonymous, four synonymous (one predicted to affect splicing). In TAC3, one homozygous single base pair deletion was identified, resulting in complete loss of the neurokinin B decapeptide. Phenotypic information was available on 16 males and seven females with coding sequence variants in TACR3/TAC3. Of the 16 males, 15 had microphallus; none of the females had spontaneous thelarche. Seven of the 16 males and five of the seven females were assessed after discontinuation of therapy; six of the seven males and four of the five females demonstrated evidence for reversibility of their hypogonadotropism.
Conclusions: Mutations in the neurokinin B pathway are relatively common as causes of hypogonadism. Although the neurokinin B pathway appears essential during early sexual development, its importance in sustaining the integrity of the hypothalamic-pituitary-gonadal axis appears attenuated over time.
While the neurokinin B pathway appears essential during early sexual development, its importance in sustaining the integrity of the hypothalamic-pituitary-gonadal axis appears attenuated over time.
THE CONSTANT GARDENERS Hughes, Virginia
Nature (London),
05/2012, Letnik:
485, Številka:
7400
Journal Article
Recenzirano
In 2010, Tremblay and her colleagues published a report on the activity of microglia in the visual cortex of young mice.\n It is also unclear whether neuronal activity influences the ...complement-tagging process, notes Carla Shatz, a neurobiologist at Stanford. A 2010 study of mouse models of trichotillomania - a psychiatric disorder characterized by compulsive hair-pulling - showed that disruption of the Hoxb8 gene, which in the brain is expressed only by certain types of microglia, caused mice to groom the fur right offtheir bodies4. The behaviour stopped after the mice received whole-body irradiation followed by a bone-marrow transplant.
PDF
