In vivo bioassay to test the pathogenicity of missense human AIP variants

Background Heterozygous germline loss-of-function mutations in the aryl hydrocarbon receptor-interacting protein gene (AIP) predispose to childhood-onset pituitary tumours. The pathogenicity of missense variants may pose difficulties for genetic counselling and family follow-up. Objective To develop an in vivo system to test the pathogenicity of human AIP mutations using the fruit fly Drosophila melanogaster. Methods We generated a null mutant of the Drosophila AIP orthologue, CG1847, a gene located on the Xchromosome, which displayed lethality at larval stage in hemizygous knockout male mutants (CG1847exon1_3 ). We tested human missense variants of ‘unknown significance’, with ‘pathogenic’ variants as positive control. Results We found that human AIP can functionally substitute for CG1847, as heterologous overexpression of human AIP rescued male CG1847exon1_3 lethality, while a truncated version of AIP did not restore viability. Flies harbouring patient-specific missense AIP variants (p.C238Y, p.I13N, p.W73R and p.G272D) failed to rescue CG1847exon1_3 mutants, while seven variants (p.R16H, p.Q164R, p.E293V, p.A299V, p.R304Q, p.R314W and p.R325Q) showed rescue, supporting a non-pathogenic role for these latter variants corresponding to prevalence and clinical data. Conclusion Our in vivo model represents a valuable tool to characterise putative disease-causing human AIP variants and assist the genetic counselling and management of families carrying AIP variants

Leczenie akromegalii w Rumunii. Jak blisko jesteśmy uzyskania kontroli nad chorobą?

Introduction: In Romania, no nationwide data for acromegaly treatment and control rate are available. Our objective was to assess the acromegaly control rate in a tertiary referral centre, which covers an important part of Romanian territory and population of patients with acromegaly. Materials and methods: We reviewed the records of all 164 patients (49 males and 115 females; median age 55 [47, 63.5] years) with newly or previously diagnosed acromegaly, who have been assessed at least once in our tertiary referral centre between January 1, 2012 and March 31, 2016. This sample represents 13.6% of the total expected 1200 Romanian patients with acromegaly and covers 82.9% of the counties in Romania. Control of acromegaly was defined as a random serum growth hormone (GH) < 1 ng/mL and an age-normalised serum insulin-like growth factor-I (IGF-I) value. The GH and IGF-I values used for calculation of the control rate were those at the last evaluation. The same assays for GH and IGF-I measurement were used in all patients. Results: There were 147 treated and 17 untreated patients. Of the 147 patients assessed after therapy, 137 (93.2%) had pituitary surgery, 116 (78.9%) were on medical treatment at the last evaluation, and 67 (45.5%) had radiotherapy. Seventy-one (48.3%) had a random GH < 1 ng/mL, 54 (36.7%) had a normalised, age-adjusted IGF-I, and 42 (28.6%) had both normal random serum GH and IGF-I. Conclusions: In Romania, acromegaly benefits from the whole spectrum of therapeutic interventions. However, the control rate remains disappointing.Wstęp: W Rumunii nie są dostępne ogólnokrajowe dane dotyczące leczenia akromegalii ani wskaźnika kontroli choroby. Badanie przeprowadzono w celu oceny wskaźnika kontroli akromegalii w ośrodku referencyjnym trzeciego stopnia, który obejmuje opieką zdrowotną znaczną część obszaru Rumunii i populacji pacjentów z akromegalią. Materiał i metody: Autorzy dokonali przeglądu danych medycznych wszystkich 164 chorych [49 mężczyzn i 115 kobiet; mediana wieku 55 lat (47; 63,5)] z noworozpoznaną lub wcześniej zdiagnozowaną akromegalią, których przynajmniej jednokrotnie zbadano w ośrodku referencyjnym trzeciego stopnia (miejsce pracy autorów) w okresie od 1 stycznia 2012 roku do 31 marca 2016 roku. Ta próba stanowiła 13,6% całej rumuńskiej populacji chorych na akromegalię szacowaną na 1200 osób i reprezentowała 82,9% okręgów administracyjnych w Rumunii. Kontrolę akromegalii definiowano jako stężenie przygodne hormonu wzrostu (growth hormone, GH) w surowicy wynoszące poniżej 1 ng/ml oraz normalizacja odpowiednio do wieku stężenia insulinopodobnego czynnika wzrostu 1 (insulin-like growth factor-1, IGF-1) w surowicy. Do obliczenia wskaźnika kontroli choroby stosowano wartości GH i IGF-1 z ostatnich pomiarów. U wszystkich pacjentów używano tych samych testów do pomiarów GH i IGF-1. Wyniki: Badanie obejmowało 147 chorych poddanych leczeniu i 17 chorych nieleczonych. Spośród 147 chorych ocenianych po terapii, u 137 (93,2%) zastosowano leczenie chirurgiczne, 116 (78,9%) w momencie ostatniej wizyty kontrolnej stosowało leczenie farmakologiczne, a 67 (45,5%) poddano radioterapii. U 71 chorych (48,3%) przygodne stężenie GH w surowicy wynosiło poniżej 1 ng/ml, u 54 (36,7%) uzyskano normalizację stężenia IGF-1 skorygowanego względem wieku, a u 42 chorych (28,6%) uzyskano normalizację obu parametrów — GH i IGF-1. Wnioski: W Rumunii u chorych na akromegalię stosuje się szerokie spektrum interwencji terapeutycznych, jednak wskaźnik kontroli choroby nadal pozostaje niezadawalający

Gęste mapowanie regionu VNTR genu insuliny w zespole policystycznych jajników w populacji kobiet z Europy Środkowej

Introduction: Insulin gene VNTR was associated with polycystic ovary syndrome (PCOS) in some studies but not in others. This couldb be due to the heterogeneity of the definition of PCOS and/or the use of inappropriate gene mapping strategies.Material and methods: In this investigation, the association of VNTR with PCOS was explored in a population of women from Central Europe (377 cases and 105 controls) in whom PCOS was diagnosed according to Rotterdam criteria. Seven SNPs: rs3842756 (G/A), rs3842755 (G/T), rs3842754 (C/T), rs3842753 (A/C), rs3842752 (C/T), rs3842748 (G/C), and rs689 (T/A) were genotyped in a portion of the population (160 cases and 95 controls) by sequencing or by SSO-PCR. Analysis of linkage disequilibrium (LD) pattern allowed selecting three tagSNPs (rs3842754, rs3842748, and rs689), which were genotyped in the rest of the population by KASPar.Results: Six haplotypes were reconstructed, among which three (h1, h2 and h6) were more frequent. Statistical analysis allowed observation of the association of the SNP rs3842748, through its GC genotype, with obesity in PCOS (P = 0.049; OR CI95% 1,59 [1.00–2.51]) and in classical PCOS (YPCOS) (P = 0.010), as well as the correlation of the SNP rs689 and the pair of haplotypes h1/h1 with higher levels of testosteronaemia in the PCOS group, although this was at the limit of significance (P = 0.054)Conclusion: These results are in accordance with some studies in literature and highlight the role of insulin gene VNTR in complex metabolic disorders. (Endokrynol Pol 2015; 66 (3): 198–206)Wstęp: W niektórych badaniach, zmienna liczba powtórzeń tandemowych (VNTR) genu insuliny była związana z zespołem policystycznych jajników (PCOS), lecz w innych taki związek nie występował. Mogło tak być z powodu heterogeniczności definicji PCOS i/lub stosowania nieprawidłowych strategii mapowania genów.Materiał i metody: W niniejszym badaniu, związek VNTR z PCOS zbadano w populacji kobiet pochodzących z Europy Środkowej (377 przypadków chorobowych oraz 105 osób kontrolnych), u których zdiagnozowano PCOS według kryteriów rotterdamskich. Siedem polimorfizmów pojedynczego nukleotydu (SNP): rs3842756 (G/A), rs3842755 (G/T), rs3842754 (C/T), rs3842753 (A/C), rs3842752 (C/T), rs3842748 (G/C), oraz rs689 (T/A) wytypowano w części populacji (160 przypadków chorobowych i 95 osób kontrolnych) poprzez sekwencjonowanie lub SSO-PCR. Analiza wzoru niezrównoważenia sprzężeń (LD) pozwoliła na selekcję trzech SNP znacznikowych (tagSNP) (rs3842754, rs3842748 i rs689), które wyselekcjonowano w pozostałej części populacji metodą KASPar.Wyniki: Sześć haplotypów odtworzono, z których 3 (h1, h2 i h6) występowały częściej. Analiza statystyczna pozwoliła na obserwację związku SNP rs3842748, poprzez genotyp GC, z otyłością w PCOS (P = 0,049; OR CI 95% 1,59 [1,00–2,51]) i klasycznym PCOS (YPCOS) (P = 0,010), jak również korelacji SNP rs689 i pary haplotypów h1/h1 z wyższym stężeniem testosteronemii w grupie PCOS, chociaż wynik ten znajdował się na granicy istotności (P = 0,054).Wnioski: Powyższe wyniki są zgodne z niektórymi badaniami w piśmiennictwie i podkreślają role VNTR genu insuliny w złożonych zaburzeniach metabolicznych. (Endokrynol Pol 2015; 66 (3): 198–206

Improvement of acromegaly control with multimodal therapy in Romania

Introduction: In Romania, there is no acromegaly national register and there are no nationwide data available. However, some studies have reported the control rates in the country’s main referral centres. Our aim was to assess the overall control rate in our tertiary referral centre. Also, we assessed the control rate in the last three years, and we compared the results with our previous reports. Material and methods: We reviewed the charts of 186 patients with acromegaly assessed in our department between January 1st, 2012 and May 31st, 2019. We also compared the control rates for patients treated between April 1st, 2016 and May 31st, 2019 with historical controls (assessed between January 1st, 2012 and March 31st, 2016). Results: Primary analysis: There were 19 untreated and 167 treated patients, mean age 52.46 years, surgery being the most commonly used treatment. The surgical cure rate was 14.8%, and disease control with medical treatment was 35.3%. Secondary analysis: In the first group there were 45 patients, surgery also being the most commonly used treatment. The surgical cure rate was 26.9%, and disease control was 30.4%. In the second group (historical controls) there were 42 patients, surgery being the most commonly used treatment. The surgical cure rate was 9.7%, and disease control with medical treatment was 15.4%. Random GH and IGF-1 after surgery were lower in the first group (p < 0.05) Conclusions: Changes in the Romanian protocol and highly specialised pituitary centres has improved the cure rate and disease control in patients with acromegaly.

In-frame seven amino-acid duplication in AIP arose over the last 3000 years, disrupts protein interaction and stability and is associated with gigantism.

Mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene are associated with pituitary adenoma, acromegaly and gigantism. Identical alleles in unrelated pedigrees could be inherited from a common ancestor or result from recurrent mutation events.EDGE Project ID: 172

Significant benefits of AIP testing and clinical screening in familial isolated and young-onset pituitary tumors

Context Germline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene are responsible for a subset of familial isolated pituitary adenoma (FIPA) cases and sporadic pituitary neuroendocrine tumors (PitNETs). Objective To compare prospectively diagnosed AIP mutation-positive (AIPmut) PitNET patients with clinically presenting patients and to compare the clinical characteristics of AIPmut and AIPneg PitNET patients. Design 12-year prospective, observational study. Participants & Setting We studied probands and family members of FIPA kindreds and sporadic patients with disease onset ≤18 years or macroadenomas with onset ≤30 years (n = 1477). This was a collaborative study conducted at referral centers for pituitary diseases. Interventions & Outcome AIP testing and clinical screening for pituitary disease. Comparison of characteristics of prospectively diagnosed (n = 22) vs clinically presenting AIPmut PitNET patients (n = 145), and AIPmut (n = 167) vs AIPneg PitNET patients (n = 1310). Results Prospectively diagnosed AIPmut PitNET patients had smaller lesions with less suprasellar extension or cavernous sinus invasion and required fewer treatments with fewer operations and no radiotherapy compared with clinically presenting cases; there were fewer cases with active disease and hypopituitarism at last follow-up. When comparing AIPmut and AIPneg cases, AIPmut patients were more often males, younger, more often had GH excess, pituitary apoplexy, suprasellar extension, and more patients required multimodal therapy, including radiotherapy. AIPmut patients (n = 136) with GH excess were taller than AIPneg counterparts (n = 650). Conclusions Prospectively diagnosed AIPmut patients show better outcomes than clinically presenting cases, demonstrating the benefits of genetic and clinical screening. AIP-related pituitary disease has a wide spectrum ranging from aggressively growing lesions to stable or indolent disease course

Familial Isolated Pituitary Adenomas Adenoame hipofizare familiale izolate

Adenoamele hipofizare sunt tumori benigne frecvente care prezintã însã o morbiditate crescutã datoratã complicaåiilor lor locale. Majoritatea cazurilor apar sporadic, dar 5% sunt familiale, asociate cu alte tumori (cum e cazul pentru MEN1 aei MEN4, Complexul Carney, Sindromul McCune-Albright) sau fãrã alte patologii asociate cum este în FIPA (Adenoame Hipofizare Familiale Izolate). AIP (proteina de interacåiune cu receptorul aril-hidrocarbon), o genã supresor tumoral, prezintã mutaåii germinale la aproximativ 30% din pacienåii FIPA aei, într-un procent mult mai mic, la adenoamele hipofizare sporadice. Pacienåii prezentând o mutaåie AIP au anumite caracteristici fenotipice: sunt mai tineri aei prezintã adenoame hipofizare mai mari, de obicei secretând hormon de creaetere sau prolactina, aei sunt mult mai rezistente la terapiile disponibile comparativ cu pacienåii care nu prezintã mutaåie AIP. Recent a fost identificatã o nouã modificare genetica la pacienåii FIPA cu gigantism debutat devreme în copilarie -microduplicaåii la nivelul cromozomului Xq26.3 iar acest sindrom a fost denumit X-LAG (acrogigantism X-linkat). Cu toate acestea în mai mult de jumãtate din cazurile de FIPA fundalul genetic al bolii nu este cunoscut aaea încât studii suplimentare sunt necesare în acestã direcåie. Cuvinte cheie: adenom hipofizar, acromegalie, genetica, AIP, FIPA Review ABSTRACT Pituitary adenomas are frequent benign tumors that cause a high morbidity due to their complications. Most cases are sporadic but 5% arise in a familial setting, associated with other tumors (as is for MEN1 and MEN4, Carney Complex, McCune-Albright Syndrome) or without other associated disease as is for FIPA (Familial Isolated Pituitary Adenomas) families. AIP (Aryl-hydrocarbon Receptor Interacting Protein), a tumor suppressor gene, is mutated in approximately 30% of FIPA patients and in a much lesser percent in sporadic pituitary adenomas. Patients harboring an AIP mutation have certain characteristics: are younger and with larger pituitary adenomas, usually secreting growth hormone or prolactin and more resistant to current therapies as compared to AIP negative patients. Recently a new genotype was identified in FIPA patients with early onset gigantism -microduplications on chromosome Xq26.3 and the syndrome was called X-LAG (X-linked acrogigantism). In more than a half of FIPA patients the genetic background of the disease is still unknown and more work is needed in this direction

Landscape of Familial Isolated and Young-Onset Pituitary Adenomas: Prospective Diagnosis in AIP Mutation Carriers.

Familial isolated pituitary adenoma (FIPA) due to aryl hydrocarbon receptor interacting protein (AIP) gene mutations is an autosomal dominant disease with incomplete penetrance. Clinical screening of apparently unaffected AIP mutation (AIPmut) carriers could identify previously unrecognized disease.This article is freely available via PubMed Central. Click on the 'Additional Link' above to access the full text