Murrosiän aikataulun geneettinen säätely

In the general population, the timing of puberty is normally distributed. This variation is determined by genetic and environmental factors, but the exact mechanisms underlying these influences remain elusive. The purpose of this study was to gain insight into genetic regulation of pubertal timing. Contributions of genetic versus environmental factors to the normal variation of pubertal timing were explored in twins. Familial occurrence and inheritance patterns of constitutional delay of growth and puberty, CDGP (a variant of normal pubertal timing), were studied in pedigrees of patients with this condition. To ultimately detect genes involved in the regulation of pubertal timing, genetic loci conferring susceptibility to CDGP were mapped by linkage analysis in the same family cohort. To subdivide the overall phenotypic variance of pubertal timing into genetic and environmental components, genetic modeling based on monozygous twins sharing 100% and dizygous twins sharing 50% of their genes was used in 2309 girls and 1828 boys from the FinnTwin 12-17 study. The timing of puberty was estimated from height growth, i.e. change in the relative height between the age when pubertal growth velocity peaks in the general population and adulthood. This reflects the percentage of adult height achieved at the average peak height velocity age, and thus, pubertal timing. Boys and girls diagnosed with CDGP were gathered through medical records from six pediatric clinics in Finland. First-degree relatives of the probands were invited to participate by letter; altogether, 286 families were recruited. When possible, families were extended to include also second-, third-, or fourth-degree relatives. The timing of puberty in all family members was primarily assessed from longitudinal growth data. Delayed puberty was defined by onset of pubertal growth spurt or peak height velocity taking place 1.5 (relaxed criterion) or 2 SD (strict criterion) beyond the mean. If growth data were unavailable, pubertal timing was based on interviews. In this case, CDGP criteria were set as having undergone pubertal development more than 2 (strict criterion) or 1.5 years (relaxed criterion) later than their peers, or menarche after 15 (strict criterion) or 14 years (relaxed criterion). Familial occurrence of strict CDGP was explored in families of 124 patients (95 males and 29 females) from two clinics in Southern Finland. In linkage analysis, we used relaxed CDGP criteria; 52 families with solely growth data-based CDGP diagnoses were selected from all clinics. Based on twin data, genetic factors explain 86% and 82% of the variance of pubertal timing in girls and boys, respectively. In families, 80% of male and 76% of female probands had affected first-degree relatives, in whom CDGP was 15 times more common than the expected (2.5%). In 74% (17 of 23) of the extended families with only one affected parent, familial patterns were consistent with autosomal dominant inheritance. By using 383 multiallelic markers and subsequently fine-mapping with 25 additional markers, significant linkage for CDGP was detected to the pericentromeric region of chromosome 2, to 2p13-2q13 (multipoint HLOD 4.44, α 0.41). The findings of the large twin study imply that the vast majority of the normal variation of pubertal timing is attributed to genetic effects. Moreover, the high frequency of dominant inheritance patterns and the large number of affected relatives of CDGP patients suggest that genetic factors also markedly contribute to constitutional delay of puberty. Detection of the locus 2p13-2q13 in the pericentromeric region of chromosome 2 associating with CDGP is one step towards unraveling the genes that determine pubertal timing.Murrosiän alkamisen ajankohta noudattaa terveessä väestössä normaalijakaumaa. Tätä vaihtelua määräävät vaikutusmekanismeiltaan osin vielä puutteellisesti tunnetut geneettiset ja ympäristötekijät. Tämän tutkimuksen tarkoituksena oli selvittää murrosiän aikataulun geneettistä säätelyä. Tervettä väestöä edustavilla kaksosilla tutkittiin geneettisen ja ympäristövaikutuksen osuutta murrosiän aikataulun normaalivaihteluun. Normaalia ääripäätä edustavan myöhäisen murrosiän esiintymistä suvuissa ja periytymismalleja tutkittiin perheaineistossa. Kytkentäanalyysillä kartoitettiin perheissä viivästyneeseen murrosikään kytkeytyviä geenialueita, mistä tulevaisuuden tavoitteena on tunnistaa murrosiän käynnistymistä sääteleviä geenejä. Tutkimuksen kaksosaineisto käsitti FinnTwin 12-17 kohortin 2309 tyttöä ja 1828 poikaa. Murrosiän normaalivaihtelu jaettiin, perustuen samanmunaisten kaksosten geneettiseen identtisyyteen erimunaisten kaksosten jakaessa vain noin 50% geeneistään, geneettisten ja ympäristötekijöiden määräämiin osuuksiin. Murrosiän aikataulun mittarina käytettiin suhteellisen pituuden muutosta aikuisiän ja väestön keskimääräisen murrosiän kasvupyrähdyksen huippunopeusiän välillä, mikä heijastaa ko. murrosiän ajankohdan jälkeen jäljellä olevaa kasvua ja siten murrosiän aikataulua. Tutkimuksen toisen aineiston muodostivat potilaat ja heidän perheensä. Konstitutionaalisesti viivästyneen murrosiän vuoksi kuudessa suomalaisessa sairaalassa tutkittuja poikia ja tyttöjä vanhempineen, sisaruksineen ja mahdollisuuksien mukaan myös kaukasempine sukulaisineen pyydettiin osallistumaan tutkimukseen. Osallistuvia perheitä oli 286. Murrosiän ajoitus perheenjäsenillä määritettiin kasvukäyriltä murrosiän kasvupyrähdyksen ajankohdan perusteella. Murrosikä todettiin viivästyneeksi, mikäli kasvupyrähdyksen alku tai huippunopeus ajoittui 1.5 tai 2 SD:ta keskimääräistä myöhäisempään ikään. Kaikki tutkittavat myös haastateltiin, mitä käytettiin hyväksi murrosiän ajankohdan määrittämisessä kasvutietojen puuttuessa. Viivästyneen murrosiän (2 SD kriteeri) periytymistä tutkittiin 124 (95 pojan, 29 tytön) pääkaupunkiseudun potilaan suvussa, kun taas kytkentäanalyysiin valittiin 52 sukua koko Suomesta. Kytkentäanalyysiin sopiviksi katsottiin suvut, joissa kasvutietoihin perustuva viivästynyt murrosikä (1.5 SD kriteeri) todettiin vain toisella potilaan vanhemmista ja osalla tämän sukulaisista. Kaksostutkimuksen perusteella murrosiän alkamisiän normaalivaihtelusta 86% (tytöt) ja 82% (pojat) on geneettisistä tekijöistä johtuvaa. Viivästyneen murrosiän vuoksi tutkituista pojista 80%:lla ja tytöistä 76%:lla todettiin samanlainen ominaisuus myös vähintään yhdellä ensimmäisen asteen sukulaisella. Näillä viivästynyttä murrosiän kasvupyrähdystä oli 15 kertaisesti väestön keskimääräiseen 2 SD:tä myöhäisempään kasvupyrähdykseen nähden (2.5%). Viivästynyt murrosikä periytyi vallitsevasti 74%:ssa (17/23) niistä kaukaisempiinkin sukulaisiin laajennetuista suvuista, joissa vain toinen potilaan vanhemmista oli murrosiässään viivästynyt. Koko genomin kartoituksella ja kytkentäanalyysillä hienokartoituksineen viivästyneeseen puberteettiin kytkeytyi merkitsevästi kromosomialue 2p13-2q13 (multipoint HLOD 4.44; α 0.41). Tutkimus osoittaa, että geneettiset tekijät määräävät suurelta osin murrosiän aikataulun normaalivaihtelua ja pääasiassa siis säätelevät murrosiän käynnistymistä. Ominaisuus kehittyä murrosiässään keskimääräistä myöhäisemmin on vahvasti perinnöllinen. Viivästyneen murrosiän usein vallitseva periytymistaipumus kertoo geneettisten tekijöiden vahvasta vaikutuksesta ilmiasuun ja mahdollisuudesta paikantaa tätä ominaisuutta määrääviä geneettisiä tekijöitä kytkentäanalyysillä. Tutkimuksessa viivästyneeseen murrosikään kytkeytyikin merkitsevästi 2p13-2q13 kromosomialue. Tämä sisältänee murrosiän alkamisen säätelyssä merkityksellisen aiemmin vielä tuntemattoman geenin, jonka tunnistaminen tulee auttamaan murrosiän aikataulun säätelyn ja vielä osin tuntemattomien murrosiän käynnistysmekanismien selvittämisessä

Neonataalihypertyreoosi

English summaryPeer reviewe

Familial central precocious puberty : two novel MKRN3 mutations

Background Paternally inherited loss-of-function mutations in MKRN3 underlie central precocious puberty (CPP). We describe clinical and genetic features of CPP patients with paternally inherited MKRN3 mutations in two independent families. Methods The single coding exon of MKRN3 was analyzed in three patients with CPP and their family members, followed by segregation analyses. Additionally, we report the patients' responses to GnRH analog treatment. Results A paternally inherited novel heterozygous c.939C>G, p.(Ile313Met) missense mutation affecting the RING finger domain of MKRN3 was found in a Finnish girl with CPP (age at presentation 6 years). Two Polish siblings (a girl presenting with B2 at the age of 4 years and a boy with adult size testes at the age of 9 years) had inherited a novel heterozygous MKRN3 mutation c.1237_1252delGGAGACACATGCTTTT p.(Gly413Thrfs*63) from their father. The girls were treated with GnRH analogs, which exhibited suppression of the hypothalamic-pituitary-gonadal axis. In contrast, the male patient was not treated, yet he reached his target height. Conclusions We describe two novel MKRN3 mutations in three CPP patients. The first long-term data on a boy with CPP due to an MKRN3 mutation questions the role of GnRH analog treatment in augmenting adult height in males with this condition. Impact We describe the genetic cause for central precocious puberty (CPP) in two families. This report adds two novel mutations to the existing literature. One of the mutations, p.(Ile313Met) affects the RING finger domain of MKRN3, which has been shown to be important for repressing the promoter activity of and . MKRN3KISS1TAC3We describe the first long-term observation of a male patient with CPP due to a paternally inherited MKRN3 loss-of-function mutation. Without GnRH analog treatment, he achieved an adult height that was in accordance with his mid-parental target height.Peer reviewe

Clinical and biochemical signs of polycystic ovary syndrome in young women born preterm

Objective: It has been suggested that adverse early life exposures increase the risk of developing polycystic ovary syndrome (PCOS) in later life. We hypothesized that women born preterm would have more biochemical and clinical signs of PCOS than women born at term. Design: The ESTER Preterm Birth Study participants were born in Northern Finland and identified from the Northern Finland Birth Cohort and the Finnish Medical Birth Register. Altogether, 74 women born very or moderately preterm (= 37 weeks, controls) were included in the analysis (mean age: 23.2 years). Methods: We measured serum total testosterone and sex hormone-binding globulin (SHBG) and calculated the free androgen index (FAI). PCOS according to the clinical and biochemical signs was defined either as hirsutism and oligoamenorrhea (via questionnaire) or as oligoamenorrhea and elevated testosterone levels (>2.4 nmol/L). Results: Women born VMPT/LPT exhibited 33.0% (8.7, 62.8)/16.4% (-2.0, 38.1) higher testosterone, 28.5% (5.3, 45.9)/24.1% (5.6, 38.9) lower SHBG levels, and 64.6% (19.4, 127.1)/42.5% (11.1, 82.9) higher FAI than controls after adjusting for age and recruitment cohort, maternal BMI, smoking, and pregnancy disorders, parental education, history of hypertension, diabetes, myocardial infarction or stroke, and subject's birth weight s.D. Odds ratios for having PCOS were 1.67 (0.44, 6.23)/3.11 (1.26, 7.70). Conclusions: Women born preterm have a more hyperandrogenic hormonal profile, and those born LPT are approximately three times more likely at risk to have PCOS compared to women born at term.Peer reviewe

EAP1 regulation of GnRH promoter activity is important for human pubertal timing

The initiation of puberty is orchestrated by an augmentation of gonadotropin-releasing hormone (GnRH) secretion from a few thousand hypothalamic neurons. Recent findings have indicated that the neuroendocrine control of puberty may be regulated by a hierarchically organized network of transcriptional factors acting upstream of GnRH. These include enhanced at puberty 1 (EAP1), which contributes to the initiation of female puberty through transactivation of the GnRH promoter. However, no EAP1 mutations have been found in humans with disorders of pubertal timing. We performed whole-exome sequencing in 67 probands and 93 relatives from a large cohort of familial self-limited delayed puberty (DP). Variants were analyzed for rare, potentially pathogenic variants enriched in case versus controls and relevant to the biological control of puberty. We identified one in-frame deletion (Ala221del) and one rare missense variant (Asn770His) in EAP1 in two unrelated families; these variants were highly conserved and potentially pathogenic. Expression studies revealed Eap1 mRNA abundance in peri-pubertal mouse hypothalamus. EAP1 binding to the GnRH1 promoter increased in monkey hypothalamus at the onset of puberty as determined by chromatin immunoprecipitation. Using a luciferase reporter assay, EAP1 mutants showed a reduced ability to trans-activate the GnRH promoter compared to wild-type EAP1, due to reduced protein levels caused by the Ala221del mutation and subcellular mislocation caused by the Asn770His mutation, as revealed by western blot and immunofluorescence, respectively. In conclusion, we have identified the first EAP1 mutations leading to reduced GnRH transcriptional activity resulting in a phenotype of self-limited DP.Peer reviewe

HS6ST1 Insufficiency Causes Self-Limited Delayed Puberty in Contrast With Other GnRH Deficiency Genes

Context: Self-limited delayed puberty (DP) segregates in an autosomal-dominant pattern, but the genetic basis is largely unknown. Although DP is sometimes seen in relatives of patients with hypogonadotropic hypogonadism (HH), mutations in genes known to cause HH that segregate with the trait of familial self-limited DP have not yet been identified. Objective: To assess the contribution of mutations in genes known to cause HH to the phenotype of self-limited DP. Design, Patients, and Setting: We performed whole-exome sequencing in 67 probands and 93 relatives from a large cohort of familial self-limited DP, validated the pathogenicity of the identified gene variant in vitro, and examined the tissue expression and functional requirement of the mouse homolog in vivo. Results: A potentially pathogenic gene variant segregating with DP was identified in 1 of 28 known HH genes examined. This pathogenic variant occurred in HS6ST1 in one pedigree and segregated with the trait in the six affected members with heterozygous transmission (P = 3.01 x 10 -5 ). Biochemical analysis showed that this mutation reduced sulfotransferase activity in vitro. Hs6st1 mRNA was expressed in peripubertal wild-type mouse hypothalamus. GnRH neuron counts were similar in Hs6st1 (+/-) and Hs6st1(+/+) mice, but vaginal opening was delayed in Hs6st1(+/-) mice despite normal postnatal growth. Conclusions: We have linked a deleterious mutation in HS6ST1 to familial self-limited DP and show that heterozygous Hs6st1 loss causes DP in mice. In this study, the observed overlap in potentially pathogenic mutations contributing to the phenotypes of self-limited DP and HH was limited to this one gene.Peer reviewe

Lipoprotein subclass profiles in young adults born preterm at very low birth weight

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Gestational Diabetes But Not Prepregnancy Overweight Predicts for Cardiometabolic Markers in Offspring Twenty Years Later

Context: Maternal gestational diabetes mellitus (GDM) and prepregnancy overweight/obesity [body mass index (BMI) >= 25 kg/m(2)] might adversely affect offspring cardiometabolic health. Objective: To assess the associations between maternal GDM and prepregnancy overweight/obesity with adult offspring cardiometabolic risk factors. Design: Longitudinal cohort study (ESTER Maternal Pregnancy Disorders Study and the Arvo Ylppo Longitudinal Study). Setting: Province of Uusimaa and Northern Finland. Participants: At a mean age of 24.1 +/- 1.3 years, we classified offspring as offspring of mothers with GDM regardless of the prepregnancy BMI (OGDM; n = 193); normoglycemic mothers with pre pregnancy overweight/obesity (ONO; n = 157); and normoglycemic mothers with prepregnancy BMI Main Outcome Measures: We assessed the cardiometabolic biomarkers from blood and measured the blood pressure at rest and heart rate. Results: Compared with the controls, the OGDM and ONO groups had greater fasting glucose (1.6%; 95% CI, 0.1% to 3.1%; and 2.3%; 95% CI, 0.5% to 4.3%, respectively) and insulin (12.7%; 95% CI, 4.4% to 21.9%; and 8.7%; 95% CI, 0.2% to 17.8%). These differences attenuated to nonsignificance when adjusted for confounders and/or current offspring characteristics, including BMI or body fat percentage. The OGDM group had lower SHBG (men, 12.4%; 95% CI, 20.2% to 3.9%; women, 33.2%; 95% CI, 46.3% to 16.8%), high-density lipoprotein (-6.6%; 95% CI, 10.9% to 2.2%), and apolipoprotein Al (-4.5%; 95% CI, 7.5% to 1.4%). These differences survived the adjustments. The heart rate and other biomarkers were similar among the groups. Conclusions: Adult offspring of mothers with GDM have increased markers of insulin resistance and a more atherogenic lipid profile. These were only partly explained by confounders or current offspring adiposity. Maternal prepregnancy overweight/obesity was associated with impaired offspring glucose regulation, which was explained by confounders and/or current adiposity.Peer reviewe

Contributions of Function-Altering Variants in Genes Implicated in Pubertal Timing and Body Mass for Self-Limited Delayed Puberty

Context: Self-limited delayed puberty (DP) is often associated with a delay in physical maturation, but although highly heritable the causal genetic factors remain elusive. Genome-wide association studies of the timing of puberty have identified multiple loci for age at menarche in females and voice break in males, particularly in pathways controlling energy balance. Objective/Main Outcome Measures: We sought to assess the contribution of rare variants in such genes to the phenotype of familial DP. Design/Patients: We performed whole-exome sequencing in 67 pedigrees (125 individuals with DP and 35 unaffected controls) from our unique cohort of familial self-limited DP. Using a whole-exome sequencing filtering pipeline one candidate gene [fat mass and obesity-associated gene (FTO)] was identified. In silico, in vitro, and mouse model studies were performed to investigate the pathogenicity of FTO variants and timing of puberty in FTO+/- mice. Results: We identified potentially pathogenic, rare variants in genes in linkage disequilibrium with genome-wide association studies of age at menarche loci in 283 genes. Of these, five genes were implicated in the control of body mass. After filtering for segregation with trait, one candidate, FTO, was retained. Two FTO variants, found in 14 affected individuals from three families, were also associated with leanness in these patients with DP. One variant (p. Leu44Val) demonstrated altered demethylation activity of the mutant protein in vitro. Fto(+/-) mice displayed a significantly delayed timing of pubertal onset (P <0.05). Conclusions: Mutations in genes implicated in body mass and timing of puberty in the general population may contribute to the pathogenesis of self-limited DP.Peer reviewe

Clinical and biochemical signs of polycystic ovary syndrome in young women born preterm

AbstractObjectiveIt has been suggested that adverse early life exposures increase the risk of developing polycystic ovary syndrome (PCOS) in later life. We hypothesized that women born preterm would have more biochemical and clinical signs of PCOS than women born at term.DesignThe ESTER Preterm Birth Study participants were born in Northern Finland and identified from the Northern Finland Birth Cohort and the Finnish Medical Birth Register. Altogether, 74 women born very or moderately preterm (MethodsWe measured serum total testosterone and sex hormone-binding globulin (SHBG) and calculated the free androgen index (FAI). PCOS according to the clinical and biochemical signs was defined either as hirsutism and oligoamenorrhea (via questionnaire) or as oligoamenorrhea and elevated testosterone levels (>2.4 nmol/L).ResultsWomen born VMPT/LPT exhibited 33.0% (8.7, 62.8)/16.4% (−2.0, 38.1) higher testosterone, 28.5% (5.3, 45.9)/24.1% (5.6, 38.9) lower SHBG levels, and 64.6% (19.4, 127.1)/42.5% (11.1, 82.9) higher FAI than controls after adjusting for age and recruitment cohort, maternal BMI, smoking, and pregnancy disorders, parental education, history of hypertension, diabetes, myocardial infarction or stroke, and subject’s birth weight s.d. Odds ratios for having PCOS were 1.67 (0.44, 6.23)/3.11 (1.26, 7.70).ConclusionsWomen born preterm have a more hyperandrogenic hormonal profile, and those born LPT are approximately three times more likely at risk to have PCOS compared to women born at term.</p