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PubMed2006

Short stature, obesity, and growth hormone deficiency in pseudohypoparathyroidism type 1a.

Albright hereditary osteodystrophy (AHO) is a genetic disorder caused by heterozygous inactivating mutations in GNAS, the gene that encodes the alpha-chain of Gs (G alpha s). This syndrome is associated with short stature, obesity, brachydactyly, and subcutaneous ossifications. Patients with GNAS mutations on maternally-inherited alleles are resistant to multiple G-protein-coupled hormones, including parathyroid hormone (PTH), thyroid-stimulating hormone (TSH), luteinizing hormone/follicle-stimulating hormone (LH/FSH), and glucagon. This variant of AHO, termed pseudohypoparathyroidism (PHP) type 1a, is due to tissue-specific paternal imprinting of G alpha s. We investigated whether patients with PHP type 1a exhibited evidence of resistance to growth hormone releasing hormone (GHRH) (1), another hormone requiring G alpha s function. In addition, G alpha s transcripts are imprinted in the pituitary somatotrophs responsible for growth hormone (GH) secretion which could thereby influence GHRH-dependent stimulation of somatotrophs. We therefore hypothesized that patients with PHP type 1a may be GH deficient which could contribute to the obesity and short stature in this condition. We found that GH deficiency is common in PHP type 1a (69%) with a prevalence that is much greater than in the general population (0.03%). We propose that GH status be evaluated in all patients with this condition. Treatment with recombinant GH could lead to improvements in height in children, as well as other physical (eg, obesity, hyperlipidemia, osteoporosis, reduced renal function) and psychological (fatigue and diminished sense of well-being) parameters in GH-deficient PHP type 1a patients of all ages.

Body Height↗

PubMed2026

Somatic genetic alterations in pituitary neuroendocrine tumors.

The molecular characterization of pituitary neuroendocrine tumors (PitNETs) has progressed pronouncedly in recent years, unraveling the molecular pathways driving initiation and progression of different PitNET types and allowing a better understanding of their biology. The most frequent recurring somatic driver alterations were recognized in corticotroph PitNETs (USP8, USP48, BRAF) and somatotroph PitNETs (GNAS) and, much less frequently, in lactotroph PitNETs (SF3B1). Additional well-characterized somatic driver alterations, including TP53, ATRX, and DAXX, are enriched in aggressive corticotroph tumors. Identification of new molecular markers and delineation of their clinical phenotypes are enabling further subclassification of PitNETs based on tumor molecular profiles, with earlier recognition of more aggressive variants. These molecular markers also provide an opportunity for new targeted therapies. Beyond single-gene alterations, epigenetic modifications, such as DNA methylation, histone modifications, and noncoding RNA dysregulation, are emerging as important contributors to PitNET pathogenesis and potential therapeutic targets. Multi-omics approaches encompassing genomics, transcriptomics, epigenomics, and proteomics are transforming PitNET classification. In this review, we provide a comprehensive, data-driven update on somatic driver alterations, epigenetic alterations, converging signaling pathways, and the related emerging therapeutic targets in PitNETs, integrating pooled analyses from published cohorts.

Humans↗

PubMed2026

Risk of Relapse and Efficacy of Adjuvant Chemotherapy in Localized Appendiceal Adenocarcinoma.

IMPORTANCE: Relapse risk and benefit of adjuvant chemotherapy after resection of appendiceal adenocarcinoma (AA) are uncertain. OBJECTIVE: To identify clinicopathologic and genomic factors associated with relapse and assess efficacy of adjuvant chemotherapy in localized AA. DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study (January 2000 through February 2024; median follow-up, 62.6 months) used Kaplan-Meier and Cox proportional hazards modeling. It took place at the University of Texas MD (UT MD) Anderson Cancer Center with validation from Memorial Sloan Kettering Cancer Center (MSKCC). Participants included a complete localized cohort of 439 patients with stage I to III AA from UT MD Anderson, of whom 202 underwent surgery at UT MD Anderson and also included a validation cohort of 128 patients with stage II AA from MSKCC. EXPOSURES: Surgical resection with or without adjuvant chemotherapy. MAIN OUTCOMES AND MEASURES: Rate of recurrence, recurrence-free survival (RFS), and overall survival (OS). RESULTS: There were 439 patients with localized AA (median age, 56.5 [IQR, 22.2-83.7] years; 50% female and 50% male) managed at MD Anderson between January 2000 and February 2024. Of 202 MDA surgical patients, 19 (9.4%) had a relapse including 9 (6%) patients with stage II and 8 (19.5%) of patients stage III disease. Five-year OS was 95.7% without vs 77.2% with relapse (hazard ratio [HR], 5.50; 95% CI, 3.07-9.83; P < .001). Relative to goblet cell tumors, mucinous (HR, 5.60; 95% CI, 2.1-15; P < .001) and enteric-type (HR, 6.60; 95% CI, 2.9-15; P < .001) histologies were independently associated with relapse, as was pathologic T4 (HR, 3.30; 95% CI, 1.9-5.7; P < .001). Importantly, poor differentiation, perforation, lymphovascular invasion, and perineural invasion, known risk factors in colorectal cancer, were not significantly associated with relapse. For the complete localized cohort, adjuvant chemotherapy was not associated with improved RFS (univariate HR, 2.06; 95% CI, 1.36-3.13; P = .001 and multivariable HR, 0.98; 95% CI, 0.43-2.28; P = .90) or OS (univariate HR, 1.80; 95% CI, 1.0-3.2; P = .04 and multivariable HR, 0.71; 95% CI, 0.24-2.1; P = .53). TP53 mutation in goblet cell tumors (HR, 6.93; 95% CI, 1.50-31.00; P = .01) and GNAS mutation in nongoblet tumors (HR, 17.0; 95% CI, 3.09-93.3; P = .001) were associated with greater risk of relapse. CONCLUSIONS AND RELEVANCE: These results demonstrate that relapse after resection of localized AA is uncommon. Molecular profiling and histopathologic subtype refine risk. Adjuvant chemotherapy were not associated with benefit.

Journal Article↗

PubMed1984

Radionuclide angiography and endomyocardial biopsy in the assessment of doxorubicin cardiotoxicity.

Thirty-eight patients with a mean age of 53.2 years (19 to 75 years of age), who were receiving doxorubicin (D) for malignant disease, were studied in order to determine the relationship between functional and morphologic myocardial changes at different dose levels. Serial patient evaluations included physical examination, chest x-ray, electrocardiogram (ECG), endomyocardial biopsy (EMB), and rest-exercise gated nuclear angiography (GNA), at doses of D ranging from 144 to 954 mg/m2 (mean, 426 mg/m2). Physical examination, chest x-ray, and ECG proved to be insensitive predictors of D cardiotoxicity. Correlation of GNA and EMB in 31 patient evaluations, exclusive of known heart disease, did not reveal any false-positive angiograms, and all abnormal GNAs were associated with abnormal biopsies. Use of stress GNA uncovered six abnormal ventricles which could have been missed with a rest GNA alone. It has been suggested that: (1) GNA is a reliable monitor of D therapy; (2) an exercise study should be performed when the rest ejection fraction is normal, but is unnecessary when the rest EF is abnormal; (3) all patients with a resting ejection fraction of less than 45%, exclusive of other cardiac disease, should have D discontinued; and (4) endomyocardial biopsy is useful in assessing D cardiotoxicity in patients with other possible causes of an abnormal GNA.

Adult↗

PubMed2005

Skeletal changes in epidermal nevus syndrome: does focal bone disease harbor clues concerning pathogenesis?

Epidermal nevus syndrome (ENS) is a rare, sporadic, congenital disorder of unknown etiology featuring a complex and highly variable phenotype that can include focal or generalized skeletal disease. We describe a young man with ENS manifesting right-sided linear skin lesions, generalized weakness, diffuse osteopenia associated with hypophosphatemic rickets, and distinctive focal bone lesions ipsilateral to the skin findings. Review of the literature concerning ENS-associated skeletal disease suggested such focal bone defects are fibrous dysplasia, but our patient did not have the typical radiographic or histopathologic findings of fibrous dysplasia. Nevertheless, his circulating fibroblast growth factor 23 (FGF-23) level was elevated, likely functioning as a "phosphatonin," yet no activating mutations in GNAS previously reported in fibrous dysplasia or McCune-Albright syndrome were detected in his leukocytes or affected skin. We postulate that the focal skeletal disease, although different than fibrous dysplasia, may be a source of FGF-23 in ENS.

Adolescent↗

PubMed2026

Clinical Utility of Trio Exome Sequencing in Rwandan Children With Autism Spectrum Disorder.

INTRODUCTION: Autism spectrum disorder (ASD) is a neurodevelopmental condition with substantial genetic and phenotypic heterogeneity. However, populations of African ancestry remain underrepresented in genomic studies, limiting understanding of ASD genetic architecture. This study aimed to characterize rare, clinically relevant genetic variants in a Rwandan pediatric ASD cohort using trio-based whole-exome sequencing (WES). METHODS: Trio-based WES was performed in 31 Rwandan pediatric patients with ASD (aged 2-18 years) and their parents. Variants were analyzed using a trio-based workflow and classified according to American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines. RESULTS: Eleven candidate variants were identified in 9 of 31 patients, including four likely pathogenic variants and seven variants of uncertain significance. This resulted in a diagnostic yield of 12.9% (4/31), expanded to 29.0% when phenotypically concordant variants of uncertain significance were considered. Most likely pathogenic variants were identified in individuals with syndromic ASD who presented with intellectual disability, epilepsy, and global developmental delay. Likely pathogenic findings included two single nucleotide variants in GABRB3, SYNGAP1, and two copy-number variants involving the GNAS locus and chromosome 1p35.3-p35.2. CONCLUSIONS: The diagnostic yield observed in this cohort is consistent with previous trio-based WES studies of ASD. The findings support the clinical utility of WES for the genetic evaluation of ASD and underscore the need for expanded genomic studies in African populations.

Humans↗

PubMed1993

Modulation of swimming behavior in the medicinal leech. II. Ionic conductances underlying serotonergic modulation of swim-gating cell 204.

In the previous paper we showed that serotonin had several effects on the electrical properties of swim-gating neurons (cells 204) of the leech. These included membrane potential depolarization, induction of a sag voltage response, and enhancement of rebound responses. Here we investigate the ionic basis of these changes by comparing responses of cell 204 to injected current pulses in experimental salines containing modified concentrations of Na+, K+, Ca2+, or Cl-. Our data indicate that serotonin modulates multiple conductances in cell 204. However, most effects of serotonin can be explained by enhancement of two Na(+)-dependent conductances, a Cs(+)-sensitive cation conductance (gh) and a persistent Na+ conductance (gNaS). Both conductances contribute to the resting potential depolarization and increased amplitude of postinhibitory rebound responses induced by serotonin. In addition, enhanced gh underlies a sag potential elicited by hyperpolarizing current pulses in serotonin-treated cells. Hyperpolarizing rebound responses following depolarizing current pulses are composed of Na(+)-dependent and Na(+)-independent components, both of which are enhanced by serotonin. Activation of an electrogenic Na+/K+ pump may underlie the prolonged Na(+)-dependent component. The Na(+)-independent component decays within 1 s and may be produced by a voltage- or Ca(2+)-activated K+ conductance.

Animals↗

PubMed1991

Mapping of the ribophorin II (RPN II) gene to human chromosome 20q12-q13.1 by in-situ hybridization.

Ribophorin I and II (RPN I and RPN II), two specific glycoproteins, span the rough regions of the endoplasmic reticulum (RER) and are thought to play an important role either in translocation or in the maintenance of RER. Studies with human-mouse somatic cell hybrids have localized the gene for RPN I on human chromosome 3q, while RPN II is on chromosome 20. Using a radioactive labelled cDNA probe, we have regionally mapped the RPN II gene to human chromosome 20q12-q13.1 by in situ hybridization. This assignment predicts a location of the murine homologue, Rpn-2, to the syntenic segment on mouse chromosome 2 in close proximity to Ada, Src and Gnas.

Chromosome Mapping↗

PubMed2006

[Calcinosis cutis in Albright hereditary osteodystrophy: pseudohypoparathyroidism type Ia].

Albright hereditary osteodystrophy (AHO) is characterized by a symptom complex including short stature, brachymetacarpia, obesity, round facies, cutaneous osteomas, and mental retardation. AHO is caused by mutations in the GNAS-gene localized on chromosome 20 encoding for Gsalpha protein, a signal transducer of endocrine pathways. Therefore, AHO is often associated with endocrinopathy such as pseudohypoparathyroidism or hypothyroidism. A nine-month-old boy presented with typical features of this syndrome. The diagnosis was confirmed by biochemical and molecular analyses. An unusual feature was calcinosis cutis at such an early age, which led to extensive differential diagnostic procedures.

Calcinosis↗

PubMed1999

Complete genome searches for quantitative trait loci controlling blood pressure and related traits in four segregating populations derived from Dahl hypertensive rats.

The Dahl salt-sensitive rat is one of the principal animal models of hereditary hypertension. Genome-wide searches were undertaken to detect quantitative trait loci (QTLs) that influence blood pressure, cardiac mass, and body weight in four F2 populations derived from Dahl salt-sensitive rats and different inbred normotensive control strains of rat. We detected three QTLs associated with one or more of the phenotypes, using a stringent statistical criterion for linkage (p < 0.00003). These included a novel QTL linked to blood pressure on rat Chromosome (Chr) 12, and another QTL on rat Chr 3 linked to body weight. A QTL on rat Chr 10 for which linkage to blood pressure has been described in other crosses was found to be a principal determinant of blood pressure and cardiac mass in some but not all of the crosses examined here. Three other regions showed evidence of linkage to these phenotypes with a less stringent statistical criterion of linkage at QTLs previously reported in other studies. As part of our study, microsatellite markers have been developed for three candidate genes for investigation in hypertension, and the genes have been localized by linkage mapping. These are: the rat Gs alpha subunit (Gnas) gene, the alpha-1B adrenergic receptor (Adra1b), and the Na+, K+-ATPase beta2 subunit (Atp1b2) gene.

Animals↗

PubMed2002

Coordinate gene expression patterns during osteoblast maturation and retinoic acid treatment of MC3T3-E1 cells.

The clonal osteoblast-like cell line MC3T3-E1 undergoes time-dependent morphological changes leading to the formation of bone nodules in vitro. Serial analysis of gene expression was used to identify genes expressed in MC3T3-E1 cells, including known osteoblast markers, structural and matrix proteins, transcription factors, cell-cycle regulators, and housekeeping genes. Relative changes in the expression of 92 representative transcripts were determined by arrayed cDNA hybridization. Complex probes were derived from MC3T3-E1 cells during the proliferation, differentiation, and matrix mineralization stages, and from cells grown with all- trans-retinoic acid (RA), a potent bone morphogen. We found that the relative expression of 68 of these genes was higher during differentiation than in the earlier proliferative phase. In the mineralization phase, all but 16 cDNAs had lower normalized hybridization intensity ratios as compared with the differentiation phase. cDNAs for vimentin (Vim), presenilin 2 (Psen2), guanine nucleotide binding protein alpha stimulating (Gnas), gap-junction membrane channel protein beta 1 (Gjb1), fibroblast growth factor receptor 1 (Fgfr1), eukaryotic translation elongation factor 2 (Eef2), and calponin 2 (Cnn2) had higher normalized hybridization intensities in both differentiation and mineralization than in proliferation. RA treatment during the differentiation phase appeared to reduce the expression of the 92 genes examined, as 62 cDNAs had lower hybridization intensities with complex cDNA probes derived from RA-treated cells than with the probe from untreated cells. Several cDNAs representing genes with previously unrecognized RA responsiveness were identified by this comparison, including the receptor for bone morphogenetic proteins 2 and 4 (Bmp2/Bmp4) and hemoglobin Y.

Activin Receptors, Type I↗

PubMed2024

Epigenetic footprints: Investigating placental DNA methylation in the context of prenatal exposure to phenols and phthalates.

BACKGROUND: Endocrine disrupting compounds (EDCs) such as phthalates and phenols can affect placental functioning and fetal health, potentially via epigenetic modifications. We investigated the associations between pregnancy exposure to synthetic phenols and phthalates estimated from repeated urine sampling and genome wide placental DNA methylation. METHODS: The study is based on 387 women with placental DNA methylation assessed with Infinium MethylationEPIC arrays and with 7 phenols, 13 phthalates, and two non-phthalate plasticizer metabolites measured in pools of urine samples collected twice during pregnancy. We conducted an exploratory analysis on individual CpGs (EWAS) and differentially methylated regions (DMRs) as well as a candidate analysis focusing on 20 previously identified CpGs. Sex-stratified analyses were also performed. RESULTS: In the exploratory analysis, when both sexes were studied together no association was observed in the EWAS. In the sex-stratified analysis, 114 individual CpGs (68 in males, 46 in females) were differentially methylated, encompassing 74 genes (36 for males and 38 for females). We additionally identified 28 DMRs in the entire cohort, 40 for females and 42 for males. Associations were mostly positive (for DMRs: 93% positive associations in the entire cohort, 60% in the sex-stratified analysis), with the exception of several associations for bisphenols and DINCH metabolites that were negative. Biomarkers associated with most DMRs were parabens, DEHP, and DiNP metabolite concentrations. Some DMRs encompassed imprinted genes including APC (associated with parabens and DiNP metabolites), GNAS (bisphenols), ZIM2;PEG3;MIMT1 (parabens, monoethyl phthalate), and SGCE;PEG10 (parabens, DINCH metabolites). Terms related to adiposity, lipid and glucose metabolism, and cardiovascular function were among the enriched phenotypes associated with differentially methylated CpGs. The candidate analysis identified one CpG mapping to imprinted LGALS8 gene, negatively associated with ethylparaben. CONCLUSIONS: By combining improved exposure assessment and extensive placental epigenome coverage, we identified several novel genes associated with the exposure, possibly in a sex-specific manner.

Humans↗

PubMed2006

Growth spurt hypocalcemia.

This is a clinical presentation of a healthy 12-year-old African-American male who had symptomatic hypocalcemia during a growth spurt that resolved after reaching a stable height. He had clinical findings consistent with Pseudohypoparathyroidism (PHP) with hypocalcemia, hyperphospatemia, and increased parathyroid hormone (PTH) concentration. We hypothesize that his family might have a hitherto unreported autosomal dominant PHP-Ib that may or may not be linked to the GNAS locus.

Body Height↗

PubMed2026

Simultaneous quantitative detection of multiple low-frequency variants by high-dynamic-range capillary electrophoresis.

Sensitive and quantitative detection of low-frequency variants across multiple loci is critical for nucleic acid-based diagnostics, yet clinical implementation requires a balance among sensitivity, multiplexing capacity, cost, and operational simplicity. We previously developed a high-dynamic-range capillary electrophoresis system capable of detecting variants at allele frequencies below 1%; however, its application was limited to single-locus analysis. Here, we expanded this platform to multiplex detection by incorporating mobility-shift strategies into the assay design. This approach enabled simultaneous analysis of 15 hotspot variants across three clinically relevant loci: KRAS codons 12 and 13 and GNAS codon 201. Validation using synthetic oligonucleotides, formalin-fixed paraffin-embedded tissue, and liquid specimens demonstrated high quantitative accuracy over clinically relevant variant allele frequency ranges, with measured values closely matching expected values (R2 > 0.97). The assay showed high concordance with targeted amplicon sequencing and digital polymerase chain reaction for all variants at variant allele frequencies ≥1%, while also detecting selected variants below this threshold. Collectively, these results establish a multiplexed high-dynamic-range capillary electrophoresis assay for simultaneous, quantitative detection of low-frequency variants, offering a scalable and cost-effective approach for disease-focused gene panels in clinical laboratory settings.

HiDy↗

PubMed2004

Evolutionary conflicts in pregnancy and calcium metabolism--a review.

The maternal-fetal unit contains three distinct haplotypes at each locus: the maternally derived fetal haplotype (MDFH) that is shared by the mother and fetus, the paternally derived fetal haplotype (PDFH), and the non-inherited maternal haplotype (NIMH). The evolutionary forces acting on these haplotypes are distinct. The NIMH is absent from the offspring and could benefit from early abortion if this enhances the probability of the mother conceiving again and producing an offspring that inherits the NIMH. This raises the possibility that some forms of recurrent spontaneous abortion may be caused by non-inherited haplotypes. Such 'selfish' behaviour would be opposed by other components of the maternal genome. Natural selection acting on genes expressed in fetuses (or their placentae) favours greater maternal investment in the fetus than does natural selection acting on genes expressed in mothers. Furthermore, in the presence of genomic imprinting, the PDFH favours greater levels of investment in the fetus than does the MDFH. These conflicts are illustrated using the example of maternal-fetal conflicts over the supply of calcium. Inactivation of the paternal copy of GNAS in proximal renal tubule is interpreted as a measure to maintain fetal bone mineralization in times of calcium stress at the expense of the maternal skeleton.

Adult↗

PubMed2005

Unbalanced placental expression of imprinted genes in human intrauterine growth restriction.

Imprinted genes control fetal and placental growth in mice and in rare human syndromes, but the role of these genes in sporadic intrauterine growth restriction (IUGR) is less well-studied. We measured the ratio of mRNA from a maternally expressed imprinted gene, PHLDA2, to that from a paternally expressed imprinted gene, MEST, by Northern blotting in 38 IUGR-associated placentae and 75 non-IUGR placentae and found an increase in the PHLDA2/MEST mRNA ratio in IUGR (p=0.0001). Altered expression of PHLDA2 and MEST was not accompanied by changes in DNA methylation within their imprinting centers, and immunohistochemistry showed PHLDA2 protein appropriately restricted to villous and intermediate cytotrophoblast in the IUGR placentae. We next did a genome-wide survey of mRNA expression in 14 IUGR placentae with maternal vascular under-perfusion compared to 15 non-IUGR placentae using Affymetrix U133A microarrays. In this series six imprinted genes were differentially expressed by ANOVA with a Benjamini-Hochberg false discovery rate of 0.05, with increased expression of PHLDA2 and decreased expression of MEST, MEG3, GATM, GNAS and PLAGL1 in IUGR placentae. At lower significance, we found IGF2 mRNA decreased and CDKN1C mRNA increased in the IUGR cases. We confirmed the significant reduction in MEG3 non-translated RNA in IUGR placentae by Northern blotting. In addition to imprinted genes, the microarray data highlighted non-imprinted genes acting in endocrine signaling (LEP, CRH, HPGD, INHBA), tissue growth (IGF1), immune modulation (INDO, PSG-family genes), oxidative metabolism (GLRX), vascular function (AGTR1, DSCR1) and metabolite transport (SLC-family solute carriers) as differentially expressed in IUGR vs. non-IUGR placentae.

Adult↗

PubMed2005

[Contribution of genetic testing after diagnosis of hypocalcemia].

Serum calcium is a fine-tuned biological value. In recent years, fundamental research and study of molecular anomalies causing certain hereditary diseases of phosphocalcium metabolism have greatly contributed to our knowledge of the factors involved in this regulation, from the embryogenesis of the parathyroid glands to the assay value of serum calcium. Targeted research on these genetic anomalies would be useful not only for the clinician, but also for the patient, contributing to the etiological search, patient follow-up, and possibly to antenatal diagnosis. The main genetic anomalies identified to date are: CaSR, GNAS, AIRE, VDR, mitochondrial DNA, 22q11 deletion.

Calcium↗

PubMed2004

Inherited ossifying diseases.

Inherited ossifying diseases are relatively uncommon diseases leading ta a great disability and life-threatening complications. Fibrodysplasia Ossificans Progressiva is characterized by the association of skeletal abnormalities mainly in great toes, and enchondral ossifications in tendons and muscles. BMP dysregulation seems to be the main underlying mechanism of the heterotopic ossifications. The genetic basis remain controversial between a mutation on chromosome 4 or 17. Progressive Osseous Heteroplasia (HOP), more recently described, shares some similarities with Albrights hereditary osteodystrophy. In HOP, the intramembranous ossifications progressively developped from the dermis to the deeper layer. The genetic abnormality involved the GNAS 1 gene leading to an inactivation of the alpha subunit of the G protein-complex. Some therapeutic approaches have been tried: angiogenesis inhibition, mast cell inhibition; others remained in project: BMP 4 inhibition; actually there is no proved efficacy of any of them.

Female↗