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1.
Artigo em Inglês | MEDLINE | ID: mdl-31730271

RESUMO

The nuclear factor one (NFI) site-specific DNA-binding proteins represent a family of transcription factors that are important for the development of multiple organ systems, including the brain. During brain development in mice, the expression patterns of Nfia, Nfib, and Nfix overlap, and knockout mice for each of these exhibit overlapping brain defects, including megalencephaly, dysgenesis of the corpus callosum, and enlarged ventricles, which implies a common but not redundant function in brain development. In line with these models, human phenotypes caused by haploinsufficiency of NFIA, NFIB, and NFIX display significant overlap, sharing neurodevelopmental deficits, macrocephaly, brain anomalies, and variable somatic overgrowth. Other anomalies may be present depending on the NFI gene involved. The possibility of variants in NFI genes should therefore be considered in individuals with intellectual disability and brain overgrowth, with individual NFI-related conditions being differentiated from one another by additional signs and symptoms. The exception is provided by specific NFIX variants that act in a dominant negative manner, as these cause a recognizable entity with more severe cognitive impairment and marked bone dysplasia, Marshall-Smith syndrome. NFIX duplications are associated with a phenotype opposite to that of haploinsufficiency, characterized by short stature, small head circumference, and delayed bone age. The spectrum of NFI-related disorders will likely be further expanded, as larger cohorts are assessed.

2.
Eur Psychiatry ; 62: 124-129, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31590015

RESUMO

BACKGROUND: Metabolic syndrome and impaired insulin sensitivity may occur as side effects of atypical antipsychotic drugs. However, studies of peripheral insulin resistance using the homeostatic model assessment of insulin resistance (HOMA-IR) or oral glucose tolerance tests (OGTT) suggest that abnormal glucose metabolism is already present in drug-naive first-episode schizophrenia (DNFES). We hypothesized impairments of neuronal insulin signaling in DNFES. METHODS: To gain insight into neuronal insulin-signaling in vivo, we analyzed peripheral blood extracellular vesicles enriched for neuronal origin (nEVs). Phosphorylated insulin signal transduction serine-threonine kinases pS312-IRS-1, pY-IRS-1, pS473-AKT, pS9-GSK3ß, pS2448-mTOR, pT389-p70S6K and respective total protein levels were determined in plasma nEVs from 48 DNFES patients and healthy matched controls after overnight fasting. RESULTS: Upstream pS312-IRS-1 was reduced at trend level (p = 0.071; this condition may amplify IRS-1 signaling). Exploratory omnibus analysis of downstream serine-threonine kinases (AKT, GSK3ß, mTOR, p70S6K) revealed lower phosphorylated/total protein ratios in DNFES vs. controls (p = 0.013), confirming decreased pathway activation. Post-hoc-tests indicated in particular a reduced phosphorylation ratio of mTOR (p = 0.027). Phosphorylation ratios of p70S6K (p = 0.029), GSK3ß (p = 0.039), and at trend level AKT (p = 0.061), showed diagnosis-dependent statistical interactions with insulin blood levels. The phosphorylation ratio of AKT correlated inversely with PANSS-G and PANSS-total scores, and other ratios showed similar trends. CONCLUSION: These findings support the hypothesis of neuronal insulin resistance in DNFES, small sample sizes notwithstanding. The counterintuitive trend towards reduced pS312-IRS-1 in DNFES may result from adaptive feedback mechanisms. The observed changes in insulin signaling could be clinically meaningful as suggested by their association with higher PANSS scores.

3.
Acta Derm Venereol ; 2019 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-31573666

RESUMO

Imbalance in skin microflora, particularly related to certain Cutibacterium acnes strains, may trigger acne. Application of non-acne-causing strains to the skin may modulate the skin microbiome and thereby lead to a reduction in acne. This pilot study evaluates the safety and efficacy of microbiome modulation on acne-prone skin. The study had 2 phases: active induction (5% benzoyl peroxide gel, 7 days) and interventional C. acnes strains treatment (5 weeks). Patients were randomized to either topical skin formulations PT1 (2 strains of C. acnes Single Locus Sequence Typing [SLST] type C3 and K8, 50% each) or PT2 (4 strains of C. acnes SLST type C3 [55%], K8 [5%], A5 [30%] and F4 [10%]). Safety and efficacy was evaluated in 14 patients (PT1=8/14, PT2=6/14). Skin microbiome composition shifted towards study formulations. No untoward adverse events, visible irritation, or significant flare-up were observed. Non-inflamed lesions and skin pH were reduced. Comedone counts improved clinically with no deterioration in inflammatory lesions.

4.
Am J Med Genet A ; 179(12): 2474-2480, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31584751

RESUMO

Noonan syndrome-like disorder with loose anagen hair (NS/LAH) is one of the RASopathies, a group of clinically related developmental disorders caused by germline mutations in genes that encode components acting in the RAS/MAPK pathway. Among RASopathies, NS/LAH (OMIM 607721) is an extremely rare, multiple anomaly syndrome characterized by dysmorphic facial features similar to those observed in Noonan syndrome along with some distinctive ectodermal findings including easily pluckable, sparse, thin, and slow-growing hair. ADA2 deficiency (DADA2, OMIM 615688) is a monogenic autoinflammatory disorder caused by homozygous or compound heterozygous mutations in ADA2, with clinical features including recurrent fever, livedo racemosa, hepatosplenomegaly, and strokes as well as immune dysregulation. This is the first report of NS/LAH and ADA2 deficiency in the same individual. We report on a patient presenting with facial features, recurrent infections and ectodermal findings in whom both the clinical and molecular diagnoses of NS/LAH and ADA2 deficiency were established, respectively.

5.
Am J Med Genet A ; 179(11): 2246-2251, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31368252

RESUMO

Adams-Oliver syndrome (AOS) is a rare congenital disease characterized by aplasia cutis congenita (ACC) and terminal transverse limb defects (TTLD). It shows significant genetic heterogeneity and can be transmitted by autosomal dominant or recessive inheritance. Recessive inheritance is associated with mutations of DOCK6 or EOGT; however, only few cases have been published so far. We present two families with EOGT-associated AOS. Due to pseudodominance in one family, the recognition of the recessive inheritance pattern was difficult. We identified two novel AOS-causing mutations (c.404G>A/p.Cys135Tyr and c.311+1G>T). The phenotype in the presented families was dominated by large ACC, whereas TTLD were mostly subtle or even absent and no major malformations occured. Our observations along with the previously published cases indicate that the two types of recessive AOS (EOGT- vs. DOCK6-associated) differ significanty regarding the frequency of neurologic or ocular deficits.

6.
Am J Hum Genet ; 104(6): 1223-1232, 2019 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-31130282

RESUMO

Aberrant signaling through pathways controlling cell response to extracellular stimuli constitutes a central theme in disorders affecting development. Signaling through RAS and the MAPK cascade controls a variety of cell decisions in response to cytokines, hormones, and growth factors, and its upregulation causes Noonan syndrome (NS), a developmental disorder whose major features include a distinctive facies, a wide spectrum of cardiac defects, short stature, variable cognitive impairment, and predisposition to malignancies. NS is genetically heterogeneous, and mutations in more than ten genes have been reported to underlie this disorder. Despite the large number of genes implicated, about 10%-20% of affected individuals with a clinical diagnosis of NS do not have mutations in known RASopathy-associated genes, indicating that additional unidentified genes contribute to the disease, when mutated. By using a mixed strategy of functional candidacy and exome sequencing, we identify RRAS2 as a gene implicated in NS in six unrelated subjects/families. We show that the NS-causing RRAS2 variants affect highly conserved residues localized around the nucleotide binding pocket of the GTPase and are predicted to variably affect diverse aspects of RRAS2 biochemical behavior, including nucleotide binding, GTP hydrolysis, and interaction with effectors. Additionally, all pathogenic variants increase activation of the MAPK cascade and variably impact cell morphology and cytoskeletal rearrangement. Finally, we provide a characterization of the clinical phenotype associated with RRAS2 mutations.

7.
Hum Mol Genet ; 2019 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-31108500

RESUMO

The RASopathies are a group of genetic syndromes caused by upregulated RAS signaling. Noonan syndrome (NS), the most common entity among the RASopathies, is characterized mainly by short stature, cardiac anomalies and distinctive facial features. Mutations in multiple RAS-MAPK pathway-related genes have been associated with NS and related phenotypes. We describe two unrelated patients presenting with hypertrophic cardiomyopathy (HCM) and dysmorphic features suggestive of NS. One of them died in the neonatal period because of cardiac failure. Targeted sequencing revealed de novo MRAS variants, c.203C > T (p.Thr68Ile) and c.67G > C (p.Gly23Arg) as causative events. MRAS has only recently been related to NS based on the observation of two unrelated affected individuals with de novo variants involving the same codons here found mutated. Gly23 and Thr68 are highly conserved residues, and the corresponding codons are known hotspots for RASopathy-associated mutations in other RAS proteins. Functional analyses documented high level of activation of MRAS mutants due to impaired GTPase activity, which was associated with constitutive plasma membrane targeting, prolonged localization in non-raft microdomains, enhanced binding to PPP1CB and SHOC2 protein, and variably increased MAPK and PI3K-AKT activation. This report provides additional evidence that a narrow spectrum of activating mutations in MRAS represents another rare cause of NS, and that MRAS has to be counted among the RASopathy genes predisposing to HCM. Moreover, our findings further emphasize the relevance of the MRAS-SHOC2-PPP1CB axis in the control of MAPK signaling, and the contribution of both MAPK and PI3K-AKT pathways in MRAS functional upregulation.

8.
Am J Med Genet A ; 179(5): 832-836, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30803155

RESUMO

Interstitial deletions within the chromosomal region 2q24.2 have already been linked to intellectual disability (ID) in the past. In most cases the described patients showed a syndromic form of ID associated with large deletions containing multiple genes. Here we describe a family with two siblings with mild non-syndromic ID. They shared the same 564 kb deletion in the chromosomal region 2q24.2 containing only the TANK gene, which was inherited from the similarly affected father, thus suggesting haploinsufficiency of TANK as a novel cause of non-syndromic ID. TANK encodes the TRAF family member-associated NF-kappa-B activator (OMIM #603893), which is expressed in many tissues. It functions as an adapter protein that interacts with the NF-kappa-B pathway and SOX11, an essential transcription factor in regeneration, survival and differentiation of the neuronal system. TANK has not been linked to ID or other human diseases before. To further elucidate the role of TANK in non-syndromic ID, we screened a cohort of 288 TANK deletion negative non-syndromic mental retardation patients for TANK mutations without identifying any pathogenic variant.

10.
Nephron ; 141(3): 156-165, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30557881

RESUMO

AIM: Aim of this study was to investigate the association of genetic variants of functional polymorphisms of matrix metalloproteinase and Cubilin (CUBN) with diabetic nephropathy (DN), end-stage renal disease (ESRD), and risk of cardiovascular disease (CVD) in Caucasian type 2 diabetes (T2D) patients. METHODS: 472 T2D-patients were genotyped for 3 single-nucleotide polymorphisms (SNPs; MMP-2 [rs2285053], MMP-9 [rs17576] and CUBN [rs1801239]). Genotyping was carried out by allelic discrimination using TaqMan SNP-genotyping-assay. RESULTS: MMP-9 (Gln279Arg) AA-genotype (OR 0.17 [0.04-0.62, p = 0.008]) and the time elapsed since diagnosis of T2D without onset of proteinuria (OR 0.87 [0.79-0.97, p = 0.008]) were found to be independently associated with reduced risk of susceptibility to DN. On the contrary higher stages of chronic kidney disease (OR 1.93 [1.15-3.23], p = 0.012) and the presence of MMP-9 GG-genotype were independently associated with DN (OR 6.07 [1.60-22.99], p = 0.008). The CUBN CC or C-risk-allele of rs1801239 was associated with ESRD (OR 2.04 [1.07-3.87], p = 0.03) and peripheral artery disease (OR 2.08 [1.12-3.88], p = 0.021). We could not find an association with MMP-2, MMP-9, or CUBN with CVD in a composite clinical endpoint model. CONCLUSIONS: This study highlights that MMP-9 or CUBN-SNPs may exert effects on risk of susceptibility to DN or ESRD. We provide novel evidence on genetic susceptibility for macroangiopathy in patients with a missense variant of CUBN (Ile2984Val) in patients with T2D.

11.
Am J Hum Genet ; 103(5): 752-768, 2018 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-30388402

RESUMO

The nuclear factor I (NFI) family of transcription factors play an important role in normal development of multiple organs. Three NFI family members are highly expressed in the brain, and deletions or sequence variants in two of these, NFIA and NFIX, have been associated with intellectual disability (ID) and brain malformations. NFIB, however, has not previously been implicated in human disease. Here, we present a cohort of 18 individuals with mild ID and behavioral issues who are haploinsufficient for NFIB. Ten individuals harbored overlapping microdeletions of the chromosomal 9p23-p22.2 region, ranging in size from 225 kb to 4.3 Mb. Five additional subjects had point sequence variations creating a premature termination codon, and three subjects harbored single-nucleotide variations resulting in an inactive protein as determined using an in vitro reporter assay. All individuals presented with additional variable neurodevelopmental phenotypes, including muscular hypotonia, motor and speech delay, attention deficit disorder, autism spectrum disorder, and behavioral abnormalities. While structural brain anomalies, including dysgenesis of corpus callosum, were variable, individuals most frequently presented with macrocephaly. To determine whether macrocephaly could be a functional consequence of NFIB disruption, we analyzed a cortex-specific Nfib conditional knockout mouse model, which is postnatally viable. Utilizing magnetic resonance imaging and histology, we demonstrate that Nfib conditional knockout mice have enlargement of the cerebral cortex but preservation of overall brain structure and interhemispheric connectivity. Based on our findings, we propose that haploinsufficiency of NFIB causes ID with macrocephaly.

12.
Mol Nutr Food Res ; : e1800076, 2018 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-30378765

RESUMO

SCOPE: Diet is amongst the most crucial factors contributing to the multistep process of carcinogenesis. The role of exogenous microRNAs (miRNAs) is still debatable. In this proof-of-principle work, the presence of miRNAs in a variety of foods, its stability to processing, and detectability in GI mucosa and feces are studied and the effect of short-term diet on human- or plant-derived miRNAs in feces and blood is examined. METHODS AND RESULTS: Animal and plant miRNAs are detected in all foods irrespective of processing. Animal-derived foods showed the highest miRNA level and the lowest is found in cheese and milk. The impact of the short-term vegetarian or meat-rich diet on blood and feces miRNA is evaluated in healthy subjects using qPCR and Affymetrix profiling. Diet is not associated with changes in ultraconserved miRNAs. However, a vegetarian diet is associated with an increase of miR-168 in feces but not in blood. Overall, plant miR-168 is detectable in normal GI mucosa and in colorectal cancer. CONCLUSIONS: Food provides a great source of miRNAs and diet may be associated with changes in xenomiRs. Plant-derived miR-168 is ubiquitously present in feces, normal mucosa, and cancer. Further studies are needed to evaluate the functional interaction between diet-derived miRNAs and GI tract.

13.
Hum Mutat ; 39(9): 1246-1261, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29924900

RESUMO

Adams-Oliver syndrome (AOS) is a rare developmental disorder, characterized by scalp aplasia cutis congenita (ACC) and transverse terminal limb defects (TTLD). Autosomal dominant forms of AOS are linked to mutations in ARHGAP31, DLL4, NOTCH1 or RBPJ, while DOCK6 and EOGT underlie autosomal recessive inheritance. Data on the frequency and distribution of mutations in large cohorts are currently limited. The purpose of this study was therefore to comprehensively examine the genetic architecture of AOS in an extensive cohort. Molecular diagnostic screening of 194 AOS/ACC/TTLD probands/families was conducted using next-generation and/or capillary sequencing analyses. In total, we identified 63 (likely) pathogenic mutations, comprising 56 distinct and 22 novel mutations, providing a molecular diagnosis in 30% of patients. Taken together with previous reports, these findings bring the total number of reported disease variants to 63, with a diagnostic yield of 36% in familial cases. NOTCH1 is the major contributor, underlying 10% of AOS/ACC/TTLD cases, with DLL4 (6%), DOCK6 (6%), ARHGAP31 (3%), EOGT (3%), and RBPJ (2%) representing additional causality in this cohort. We confirm the relevance of genetic screening across the AOS/ACC/TTLD spectrum, highlighting preliminary but important genotype-phenotype correlations. This cohort offers potential for further gene identification to address missing heritability.

14.
Hum Mutat ; 39(9): 1226-1237, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29897170

RESUMO

Malan syndrome is an overgrowth disorder described in a limited number of individuals. We aim to delineate the entity by studying a large group of affected individuals. We gathered data on 45 affected individuals with a molecularly confirmed diagnosis through an international collaboration and compared data to the 35 previously reported individuals. Results indicate that height is > 2 SDS in infancy and childhood but in only half of affected adults. Cardinal facial characteristics include long, triangular face, macrocephaly, prominent forehead, everted lower lip, and prominent chin. Intellectual disability is universally present, behaviorally anxiety is characteristic. Malan syndrome is caused by deletions or point mutations of NFIX clustered mostly in exon 2. There is no genotype-phenotype correlation except for an increased risk for epilepsy with 19p13.2 microdeletions. Variants arose de novo, except in one family in which mother was mosaic. Variants causing Malan and Marshall-Smith syndrome can be discerned by differences in the site of stop codon formation. We conclude that Malan syndrome has a well recognizable phenotype that usually can be discerned easily from Marshall-Smith syndrome but rarely there is some overlap. Differentiation from Sotos and Weaver syndrome can be made by clinical evaluation only.

15.
Nat Commun ; 9(1): 1960, 2018 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-29773874

RESUMO

No efficient treatment exists for nephrotic syndrome (NS), a frequent cause of chronic kidney disease. Here we show mutations in six different genes (MAGI2, TNS2, DLC1, CDK20, ITSN1, ITSN2) as causing NS in 17 families with partially treatment-sensitive NS (pTSNS). These proteins interact and we delineate their roles in Rho-like small GTPase (RLSG) activity, and demonstrate deficiency for mutants of pTSNS patients. We find that CDK20 regulates DLC1. Knockdown of MAGI2, DLC1, or CDK20 in cultured podocytes reduces migration rate. Treatment with dexamethasone abolishes RhoA activation by knockdown of DLC1 or CDK20 indicating that steroid treatment in patients with pTSNS and mutations in these genes is mediated by this RLSG module. Furthermore, we discover ITSN1 and ITSN2 as podocytic guanine nucleotide exchange factors for Cdc42. We generate Itsn2-L knockout mice that recapitulate the mild NS phenotype. We, thus, define a functional network of RhoA regulation, thereby revealing potential therapeutic targets.

16.
Genet Med ; 20(10): 1175-1185, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29469822

RESUMO

PURPOSE: To characterize the molecular genetics of autosomal recessive Noonan syndrome. METHODS: Families underwent phenotyping for features of Noonan syndrome in children and their parents. Two multiplex families underwent linkage analysis. Exome, genome, or multigene panel sequencing was used to identify variants. The molecular consequences of observed splice variants were evaluated by reverse-transcription polymerase chain reaction. RESULTS: Twelve families with a total of 23 affected children with features of Noonan syndrome were evaluated. The phenotypic range included mildly affected patients, but it was lethal in some, with cardiac disease and leukemia. All of the parents were unaffected. Linkage analysis using a recessive model supported a candidate region in chromosome 22q11, which includes LZTR1, previously shown to harbor mutations in patients with Noonan syndrome inherited in a dominant pattern. Sequencing analyses of 21 live-born patients and a stillbirth identified biallelic pathogenic variants in LZTR1, including putative loss-of-function, missense, and canonical and noncanonical splicing variants in the affected children, with heterozygous, clinically unaffected parents and heterozygous or normal genotypes in unaffected siblings. CONCLUSION: These clinical and genetic data confirm the existence of a form of Noonan syndrome that is inherited in an autosomal recessive pattern and identify biallelic mutations in LZTR1.

18.
Am J Med Genet A ; 176(2): 470-476, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29271604

RESUMO

Noonan syndrome is characterized by typical craniofacial dysmorphism, postnatal growth retardation, congenital heart defect, and learning difficulties and belongs to the RASopathies, a group of neurodevelopmental disorders caused by germline mutations in genes encoding components of the RAS-MAPK pathway. Mutations in the RAF1 gene are associated with Noonan syndrome, with a high prevalence of hypertrophic cardiomyopathy (HCM). RAF1 mutations cluster in exons encoding the conserved region 2 (CR2), the kinase activation segment of the CR3 domain, and the C-terminus. We present two boys with Noonan syndrome and the identical de novo RAF1 missense variant c.1082G>C/p.(Gly361Ala) affecting the CR3, but located outside the kinase activation segment. The p.(Gly361Ala) mutation has been identified as a RAF1 allele conferring resistance to RAF inhibitors. This amino acid change favors a RAF1 conformation that allows for enhanced RAF dimerization and increased intrinsic kinase activity. Both patients with Noonan syndrome showed typical craniofacial dysmorphism, macrocephaly, and short stature. One individual developed HCM and was diagnosed with a disseminated oligodendroglial-like leptomeningeal tumor (DOLT) of childhood at the age of 9 years. While there is a well-established association of NS with malignant tumors, especially childhood hemato-oncological diseases, brain tumors have rarely been reported in Noonan syndrome. Our data demonstrate that mutation scanning of the entire coding region of genes associated with Noonan syndrome is mandatory not to miss rare variants located outside the known mutational hotspots.

19.
Nat Genet ; 49(10): 1529-1538, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28805828

RESUMO

Galloway-Mowat syndrome (GAMOS) is an autosomal-recessive disease characterized by the combination of early-onset nephrotic syndrome (SRNS) and microcephaly with brain anomalies. Here we identified recessive mutations in OSGEP, TP53RK, TPRKB, and LAGE3, genes encoding the four subunits of the KEOPS complex, in 37 individuals from 32 families with GAMOS. CRISPR-Cas9 knockout in zebrafish and mice recapitulated the human phenotype of primary microcephaly and resulted in early lethality. Knockdown of OSGEP, TP53RK, or TPRKB inhibited cell proliferation, which human mutations did not rescue. Furthermore, knockdown of these genes impaired protein translation, caused endoplasmic reticulum stress, activated DNA-damage-response signaling, and ultimately induced apoptosis. Knockdown of OSGEP or TP53RK induced defects in the actin cytoskeleton and decreased the migration rate of human podocytes, an established intermediate phenotype of SRNS. We thus identified four new monogenic causes of GAMOS, describe a link between KEOPS function and human disease, and delineate potential pathogenic mechanisms.


Assuntos
Hérnia Hiatal/genética , Microcefalia/genética , Complexos Multiproteicos/genética , Mutação , Nefrose/genética , Animais , Apoptose/genética , Sistemas CRISPR-Cas , Proteínas de Transporte/genética , Movimento Celular , Citoesqueleto/ultraestrutura , Reparo do DNA/genética , Estresse do Retículo Endoplasmático/genética , Técnicas de Inativação de Genes , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/deficiência , Peptídeos e Proteínas de Sinalização Intracelular/genética , Metaloendopeptidases/deficiência , Metaloendopeptidases/genética , Camundongos , Modelos Moleculares , Síndrome Nefrótica/genética , Síndrome Nefrótica/patologia , Podócitos/metabolismo , Podócitos/ultraestrutura , Conformação Proteica , Proteínas Serina-Treonina Quinases/deficiência , Proteínas Serina-Treonina Quinases/genética , Processamento Pós-Transcricional do RNA/genética , RNA de Transferência/metabolismo , Homeostase do Telômero/genética , Peixe-Zebra , Proteínas de Peixe-Zebra/deficiência , Proteínas de Peixe-Zebra/genética
20.
Klin Padiatr ; 229(5): 267-273, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28806841

RESUMO

Objective Growth hormone (GH) deficiency (GHD) is commonly treated with recombinant human GH (rhGH). Individual response to rhGH therapy varies widely and there is evidence that variations in growth-related genes, e. g. the GH receptor (GHR) gene, may impact treatment response. We aimed to identify genetic polymorphisms which could serve as predictive markers of response to rhGH therapy. Methods We conducted a genetic analysis of single nucleotide polymorphisms (SNPs) and the GHR exon 3 deletion in 101 paediatric GHD patients receiving rhGH. Patients were analysed for 13 known SNPs in 11 genes of the GH axis (SOS1, IGFR1, GAB1, LHX4, IGFBP3, GRB10, GHRHR, GHSR), growth plate (VDR, ESR1) and cell cycle (CDK4). Individual index of responsiveness (IoR) values were compared by genotype. We also analysed the potential association between the IoR and the GHR exon 3 deletion. IoRs were analysed by genotype by one-way analysis of variance and unpaired t-test. Results Variations in two SNPs, rs2888586 (SOS1) and rs2069502 (CDK4), and the GHR exon 3 deletion were significantly associated with response to rhGH treatment. Conclusions Genetic variations are potentially suitable as predictive markers of rhGH treatment response in GHD. Genetic analysis provides a starting point for individualised treatment of GHD.

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