Genetikai tényezők a hypopituitarsmus kialakulásában. A transzkripciós faktorok szerepe az agyalapimirígy-elégtelenség hátterében

Absztrakt: A hypothalamohypophysealis rendszer fejlődési rendellenességei klinikai megjelenésükben sokszínű hypophysiselégtelenséggel járhatnak. Ezen fejlődési rendellenességek jelentős részét a hypophysis organogenezisét szabályozó transzkripciós faktorok genetikai hibái okozhatják. Az agyalapi mirigy fejlődésének korai szakaszában expresszálódó transzkripciós faktorokat kódoló gének mutációi olyan összetett fejlődési rendellenességekhez vezethetnek, amelyekben a hypopituitarismushoz egyéb központi idegrendszeri malformációk is társulnak. Az organogenezis későbbi szakaszát szabályozó transzkripciós faktorok genetikai eltérései jellemzően többszörös, ritkán izolált agyalapi mirigy hormonhiányt okoznak extrahypophysealis manifesztáció nélkül. A hypophysistranszkripciós faktorok genetikai defektusainak azonosítása segítséget adhat a hormonhiányok előrejelzésében és az érintett családtagok szűrésében. Egyes hypophysistranszkripciós faktorok expressziója felnőttkorban is kimutatható, aminek fontos klinikai jelentősége van a hypophysisadenomák WHO által ajánlott új rendszerű, ezen faktorok expresszióját is figyelembe vevő osztályozásában. Orv Hetil. 2018; 159(7): 278–284. | Abstract: Developmental disorders affecting the hypothalamic-pituitary system can result in pituitary hormone deficiency showing a diverse clinical presentation. A significant majority of these disorders are closely linked to defects in transcription factor genes which play a major role in pituitary development. Those affecting the early phase of organogenesis typically lead to complex conditions affecting the pituitary as well as structures in the central nervous system. Transcription factors involved in the late phase can result in combined but rarely isolated pituitary hormone deficiency without extra-pituitary manifestation. Identifying the defects in these pituitary transcription factor genes may provide a useful tool in predicting disease progression as well as screening family members. Several pituitary transcription factors can be detected in the adult gland as well which is strongly emphasized in the World Health Organization’s most recent guideline for pituitary tumor classification. Our review summarizes the current essential knowledge relevant for clinical endocrinologists. Orv Hetil. 2018; 159(7): 278–284

Novel frameshift mutation of the NR0B1(DAX1) in two tall adult brothers

NR0B1 (nuclear receptor subfamily 0, group B, member 1) is a transcription factor encoded by DAX1 (dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1) responsible for the development and maintenance of the steroidogenic tissues. In humans the DAX1 mutations cause congenital adrenal hypoplasia (AHC) and hypogonadotropic hypogonadism (HHG) in boys. Here we report two brothers who were assessed by endocrinologist at the age of 51 and 43 because of their serious osteoporosis. They had been substituted with prednisolone since the age of 4 and 9 years because of their primary adrenal insufficiency (PAI). Due to their late puberty caused by HHG at the age of 16 and 17 years their heights were - 3.1 and - 3.3 SD, but then they had a significant growth during their adulthood and reached the + 1.85 SD and + 3.78 SD respectively. During this period, they received glucocorticoid supplementation, but the treatment of their HHG was inadequate. At the age of 51 and 43 years insulin tolerance test (ITT) and gonadotropin releasing hormone (GnRH) test confirmed their PAI and HHG. Genetic test performed at this time revealed a novel, four nucleotides deletion (del.586-571c.GGGC or 572-575c.GGGC) of DAX1 gene. The two brothers with AHC and HHG caused by a novel DAX1 mutation, reached tall final heights, despite of the disadvantageous prednisolone treatment during their childhood. We assume that the long-term lack of the sexual hormone substitution was a significant reason of their above average height as well as their serious osteoporosis

Az extracelluláris kalciumkoncentráció érzékelése egészséges és kóros állapotokban = Extracellular calcium sensing under normal and pathological conditions

Régóta ismert, hogy az ionos kalcium fontos sejten belüli másodlagos hírvivő szerepet tölt be. Az utóbbi 15 évben megismert kísérletes vizsgálatok és klinikai tanulmányok eredményei alapján az is egyértelművé vált, hogy az ionos kalcium elsődleges jelként is működik: az extracelluláris kalciumion egy G-fehérjéhez kapcsolódó sejtfelszíni receptort aktivál, amit kalciumérzékelő receptornak neveztek el. A szerzők összefoglalják a kalciumérzékelő receptor szerepét a kalciumhomeosztázis fenntartásában, ismertetik a receptor működésének szövetspecifikus sajátosságait és azokat a kórképeket, amelyek a kalciumérzékelés zavarával járnak. A kalciumérzékelő receptor génjének funkcióvesztést vagy fokozott működést okozó csírasejtes mutációi hyper- vagy hypocalcaemiával járó öröklődő betegségeket váltanak ki. Az inaktiváló hatású mutációk heterozigóta formában familiáris hypocalciuriás hypercalcaemiát, míg homozigóta formában a gyakran életet veszélyeztető újszülöttkori hyperparathyreosist okozzák. Az autoszomális domináns hypocalcaemia hátterében aktiváló mutációk állnak. A szerzők összefoglalják ezeknek a betegségeknek a klinikai és laboratóriumi jellemzőit és a kezelés lehetőségeit. Áttekintik azokat a molekuláris folyamatokat, amelyek primer és szekunder hyperparathyreosisos betegekben hibás kalciumérzékelést váltanak ki, valamint azokat a klinikai vizsgálatokat, amelyek a kalciumérzékelő receptorgén genetikai variációinak funkcionális következményeiről számolnak be. | Ionic calcium has been known as an important intracellular second messenger for many decades. In addition, a whole series of experimental and clinical studies from the past fifteen years have provided evidence that extracellular ionic calcium itself is also a first messenger, since it is the ligand of a cell surface G-protein coupled receptor called calcium-sensing receptor. This review summarizes the current knowledge on the role of calcium-sensing receptor in the maintenance of calcium homeostasis, its functions in various tissues and some of the most important disorders characterized by defective calcium sensing. The inherited disorders of the calcium-sensing receptors may be classified as the results of loss-of-function and gain-of-function mutations of the calcium-sensing receptor gene. Loss-of-function heterozygous mutations lead to familial hypocalciuric hypercalcemia while homozygous mutations result in the frequently life-threatening disorder called neonatal severe hyperparathyroidism. Gain-of-function mutations of this receptor’s gene cause the disorder called autosomal dominant hypocalcemia. The authors briefly highlight the clinical features, laboratory characteristics and therapeutic implications of these disorders. Also, they discuss briefly the molecular mechanisms resulting defective calcium-sensing in of patients with primary and secondary hyperparathyroidism, and summarize the results of some recent investigations on the functional consequences of genetic variants of the calcium-sensing receptor gene

Loss of Function of the Nuclear Receptor NR2F2, Encoding COUP-TF2, Causes Testis Development and Cardiac Defects in 46,XX Children

Emerging evidence from murine studies suggests that mammalian sex determination is the outcome of an imbalance between mutually antagonistic male and female regulatory networks that canalize development down one pathway while actively repressing the other. However, in contrast to testis formation, the gene regulatory pathways governing mammalian ovary development have remained elusive. We performed exome or Sanger sequencing on 79 46,XX SRY-negative individuals with either unexplained virilization or with testicular/ovotesticular disorders/differences of sex development (TDSD/OTDSD). We identified heterozygous frameshift mutations in NR2F2, encoding COUP-TF2, in three children. One carried a c.103_109delGGCGCCC (p.Gly35Argfs( *)75) mutation, while two others carried a c.97_103delCCGCCCG (p.Pro33Alafs( *)77) mutation. In two of three children the mutation was de novo. All three children presented with congenital heart disease (CHD), one child with congenital diaphragmatic hernia (CDH), and two children with blepharophimosis-ptosis-epicanthus inversus syndrome (BPES). The three children had androgen production, virilization of external genitalia, and biochemical or histological evidence of testicular tissue. We demonstrate a highly significant association between the NR2F2 loss-of-function mutations and this syndromic form of DSD (p = 2.44 x 10(-8)). We show that COUP-TF2 is highly abundant in a FOXL2-negative stromal cell population of the fetal human ovary. In contrast to the mouse, these data establish COUP-TF2 as a human "pro-ovary" and "anti-testis" sex-determining factor in female gonads. Furthermore, the data presented here provide additional evidence of the emerging importance of nuclear receptors in establishing human ovarian identity and indicate that nuclear receptors may have divergent functions in mouse and human biology

Pathogenic variants in the DEAH-box RNA helicase DHX37 are a frequent cause of 46,XY gonadal dysgenesis and 46,XY testicular regression syndrome

XY individuals with disorders/differences of sex development (DSD) are characterized by reduced androgenization caused, in some children, by gonadal dysgenesis or testis regression during fetal development. The genetic etiology for most patients with 46,XY gonadal dysgenesis and for all patients with testicular regression syndrome (TRS) is unknown

Genome of Herbaspirillum seropedicae Strain SmR1, a Specialized Diazotrophic Endophyte of Tropical Grasses

The molecular mechanisms of plant recognition, colonization, and nutrient exchange between diazotrophic endophytes and plants are scarcely known. Herbaspirillum seropedicae is an endophytic bacterium capable of colonizing intercellular spaces of grasses such as rice and sugar cane. The genome of H. seropedicae strain SmR1 was sequenced and annotated by The Paraná State Genome Programme—GENOPAR. The genome is composed of a circular chromosome of 5,513,887 bp and contains a total of 4,804 genes. The genome sequence revealed that H. seropedicae is a highly versatile microorganism with capacity to metabolize a wide range of carbon and nitrogen sources and with possession of four distinct terminal oxidases. The genome contains a multitude of protein secretion systems, including type I, type II, type III, type V, and type VI secretion systems, and type IV pili, suggesting a high potential to interact with host plants. H. seropedicae is able to synthesize indole acetic acid as reflected by the four IAA biosynthetic pathways present. A gene coding for ACC deaminase, which may be involved in modulating the associated plant ethylene-signaling pathway, is also present. Genes for hemagglutinins/hemolysins/adhesins were found and may play a role in plant cell surface adhesion. These features may endow H. seropedicae with the ability to establish an endophytic life-style in a large number of plant species

Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects

Copy number variants (CNVs) have been strongly implicated in the genetic etiology of schizophrenia (SCZ). However, genome-wide investigation of the contribution of CNV to risk has been hampered by limited sample sizes. We sought to address this obstacle by applying a centralized analysis pipeline to a SCZ cohort of 21,094 cases and 20,227 controls. A global enrichment of CNV burden was observed in cases (OR=1.11, P=5.7×10−15), which persisted after excluding loci implicated in previous studies (OR=1.07, P=1.7 ×10−6). CNV burden was enriched for genes associated with synaptic function (OR = 1.68, P = 2.8 ×10−11) and neurobehavioral phenotypes in mouse (OR = 1.18, P= 7.3 ×10−5). Genome-wide significant evidence was obtained for eight loci, including 1q21.1, 2p16.3 (NRXN1), 3q29, 7q11.2, 15q13.3, distal 16p11.2, proximal 16p11.2 and 22q11.2. Suggestive support was found for eight additional candidate susceptibility and protective loci, which consisted predominantly of CNVs mediated by non-allelic homologous recombination

Schizophrenia-associated somatic copy-number variants from 12,834 cases reveal recurrent NRXN1 and ABCB11 disruptions

While germline copy-number variants (CNVs) contribute to schizophrenia (SCZ) risk, the contribution of somatic CNVs (sCNVs)—present in some but not all cells—remains unknown. We identified sCNVs using blood-derived genotype arrays from 12,834 SCZ cases and 11,648 controls, filtering sCNVs at loci recurrently mutated in clonal blood disorders. Likely early-developmental sCNVs were more common in cases (0.91%) than controls (0.51%, p = 2.68e−4), with recurrent somatic deletions of exons 1–5 of the NRXN1 gene in five SCZ cases. Hi-C maps revealed ectopic, allele-specific loops forming between a potential cryptic promoter and non-coding cis-regulatory elements upon 5′ deletions in NRXN1. We also observed recurrent intragenic deletions of ABCB11, encoding a transporter implicated in anti-psychotic response, in five treatment-resistant SCZ cases and showed that ABCB11 is specifically enriched in neurons forming mesocortical and mesolimbic dopaminergic projections. Our results indicate potential roles of sCNVs in SCZ risk

A cerebrális állományvérzés diagnosztikája a computertomográfia korszaka előtt | Diagnosis of cerebral hemorrhage before the era of computed tomography

Bevezetés: Az elmúlt évtizedekben a neurológiai képalkotás nagyot fejlődött. A koponya-CT napi rutinná vált, és a modern készülékek azonnal diagnosztizálják a parenchymás állományvérzést. Elődeink csupán az anamnézisre, a neurológiai vizsgálatra, a percutan angiográfiára és a liquorvételre támaszkodhattak annak eldöntésekor, hogy ischaemiával vagy liquortérbe nem törő állományvérzéssel állnak-e szemben. Diagnosztikus próbálkozásaik megbízhatóságát viszont az általános és cerebrális bonclelettel ellenőrizhették. Célkitűzés: A szerzők arra a kérdésre kerestek választ, hogy a liquorvizsgálat alapján milyen biztonsággal különíthető el az agyállományi vérzés és lágyulás. Módszer: A retrospektív vizsgálatot 200 akut stroke-betegen végezték, akiknél nemcsak felvételi liquorvétel, hanem később agyboncolás is történt. Eredmények: Ha a felvételi liquor véres vagy xanthochrom volt, a pozitív prediktív érték (a boncolás valóban vérzést vagy vérzéses lágyulást igazolt) 87,5%, míg a víztiszta liquor pozitív prediktív értéke (a boncolás valóban lágyulást igazolt) 90,7% volt. Az agyboncolás során liquortérbe nem törő állományvérzésnek bizonyuló, de felvételkor víztiszta liquorú betegekben a liquor fehérjetartalma magasabb volt a lágyult csoporthoz képest, de a különbség nem volt szignifikáns (p = 0,09). Következtetések: Az eredmények igazolják a klinikopatológiai vizsgálatok fontosságát. A szerzők munkájukat tisztelgésnek szánják azon elődök előtt, akik sokat tettek a magyar és ezen belül a debreceni neuropatológia fejlődéséért. Idén emlékezünk Sántha Kálmán születésének 110. és halálának 60. évfordulójára, Molnár László professzor pedig 2013-ban lenne 90 éves. Orv. Hetil., 2013, 154, 1743–1746. | Introduction: During the past decades there has been a great progress in neuroimaging methods. Cranial computed tomography is part of the daily routine now and its use allows a fast diagnosis of parenchymal hemorrhage. However, before the availability of computed tomography the differentiation between ischemic and hemorrhagic stroke was based on patient history, physical examination, percutan angiography and cerebrospinal fluid sampling, and the clinical utility could be evaluated by autopsy of deceased patients. Aim: The authors explored the diagnostic performance of cerebrospinal fluid examination for the diagnosis of ischemic and hemorrhagic stroke. Method: Data of 200 deceased stroke patients were retrospectively evaluated. All patients had liquor sampling at admission and all of them had brain autopsy. Results: Bloody or yellowish cerebrospinal fluid at admission had a positive predictive value of 87.5% for hemorrhagic stroke confirmed by autopsy, while clear cerebrospinal fluid had positive predictive value of 90.7% for ischemic stroke. Patients who had clear liquor, but autopsy revealed hemorrhagic stroke had higher protein level in the cerebrospinal fluid, but the difference was not statistically significant (p = 0.09). Conclusions: The results confirm the importance of pathological evaluation of the brain in cases deceased from cerebral stroke. With this article the authors wanted to salute for those who contributed to the development of the Hungarian neuropathology. In this year we remember the 110th anniversary of the birth, and the 60th anniversary of the death of professor Kálmán Sántha. Professor László Molnár would be 90 years old in 2013. Orv. Hetil., 154 (44), 1743–1746