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Molecular Biology Reports Mar 2016Donohue syndrome (DS) is a very rare autosomal recessive disease affecting less than one in a million life births. It represents the most severe form of insulin...
Donohue syndrome (DS) is a very rare autosomal recessive disease affecting less than one in a million life births. It represents the most severe form of insulin resistance due to mutations involving the insulin receptor (IR) gene "INSR". DS is characterized by pre- and postnatal growth retardation with failure-to-thrive, lipoatrophy, acanthosis nigricans, hypertrichosis, and dysmorphic features. An exhaustive INSR gene sequencing was performed after PCR amplification of coding exons and introns boundaries. Bioinformatic tools, including ESEfinder, MFOLD and Proter software were also used to predict the impact of INSR mutation on INSR on gene expression as well as on the protein structure and function. The results have shown a novel unusual c.3003_3012delinsGGAAG (p.S1001_D1004delinsRE) insertion/deletion (indel) mutation within the exon 16 in the three patients, which represent the fourth indel mutation within the INSR gene. The mutation modifies the secondary structure of DNA and RNA, as well as the composition of exonic splicing enhancers of exon 16. Moreover, despite the conservation of the secondary structure of the IR, the p.S1001_D1004delinsRE in-frame mutation is accompanied by the loss of four amino acids replaced by two residues of different nature and hydrophobicity level in the juxtamembrane domain of the receptor. The results have confirmed the role of the juxtamembrane domain of IR involved in a crucial interaction of the IR with cellular effectors essentially the IR substrate 1 (IRS-1), the SHC and the Nck proteins that ensure the signal mediated by the insulin transduction pathway in target cells. Our findings have also proven the genotype/phenotype correlation between INSR mutation and DS phenotype severity.
Topics: Adaptor Proteins, Signal Transducing; Africa; Amino Acid Sequence; Antigens, CD; Donohue Syndrome; Female; Gene Expression; Humans; INDEL Mutation; Infant; Infant, Newborn; Insulin Receptor Substrate Proteins; Male; Molecular Sequence Data; Oncogene Proteins; Protein Structure, Secondary; Receptor, Insulin; Sequence Alignment; Sequence Analysis, DNA; Shc Signaling Adaptor Proteins; Signal Transduction
PubMed: 26874853
DOI: 10.1007/s11033-016-3951-9 -
Journal of Clinical Research in... Aug 2023Mutations in the gene result in rare inherited syndromes causing insulin resistance, such as leprechaunism (Donohue syndrome), Rabson-Mendenhall syndrome and insulin...
Mutations in the gene result in rare inherited syndromes causing insulin resistance, such as leprechaunism (Donohue syndrome), Rabson-Mendenhall syndrome and insulin resistance type A. Leprechaunism is an autosomal recessive disorder associated with extreme insulin resistance that leads to hyperinsulinemia, impaired glucose homeostasis, fasting hypoglycemia and postprandial hyperglycemia. Impaired insulin action causes prenatal and postnatal growth retardation. Lipoatrophy, dysmorphic facies, hypertrichosis, macrogenitosomia and hypertrophy of internal organs are also present. A male infant with congenital insulin resistance was born at term after a normal pregnancy with a weight of 1905 g (<3 c), a length of 48 cm (<3 c), and an Apgar score of 10. Intrauterine growth retardation, transient hypoglycemia, pneumonia, urinary tract infection and heart defects [patent foramen ovale (PFO); patent ductus arteriosus (PDA)] were diagnosed after birth. At 5 weeks of age, he was admitted to the regional hospital with severe fever, diarrhea and dehydration. Hyperglycemia was observed (672 mg/dL), and insulin was administered. He was referred to a hospital at 7 weeks of age for suspected neonatal diabetes and hypertrophic cardiomyopathy. The physical examination revealed a loud systolic heart murmur, tachycardia, tachypnea, dysmorphic facies, hypertrichosis, acanthosis nigricans, hypotonia, swollen nipples and enlarged testicles. Glycemic fluctuations (50-250 mg/dL) were observed. The serum insulin concentration was high (maximum 1200 IU/mL) at normoglycemia. Ultrasound of the heart confirmed progressive hypertrophic cardiomyopathy. Leprechaunism was confirmed by genetic analysis of , in which a novel c.320C>G; p. Thr107Arg homozygous missense mutation was found in exon 2.
Topics: Female; Humans; Infant; Infant, Newborn; Male; Antigens, CD; Cardiomyopathy, Hypertrophic; Diabetes Mellitus; Donohue Syndrome; Facies; Hyperglycemia; Hypertrichosis; Hypoglycemia; Insulin; Insulin Resistance; Mutation; Receptor, Insulin
PubMed: 34965699
DOI: 10.4274/jcrpe.galenos.2021.2021.0256 -
Med (New York, N.Y.) Nov 2023Individuals vaccinated against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), when infected, can still develop disease that requires hospitalization. It...
BACKGROUND
Individuals vaccinated against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), when infected, can still develop disease that requires hospitalization. It remains unclear whether these patients differ from hospitalized unvaccinated patients with regard to presentation, coexisting comorbidities, and outcomes.
METHODS
Here, we use data from an international consortium to study this question and assess whether differences between these groups are context specific. Data from 83,163 hospitalized COVID-19 patients (34,843 vaccinated, 48,320 unvaccinated) from 38 countries were analyzed.
FINDINGS
While typical symptoms were more often reported in unvaccinated patients, comorbidities, including some associated with worse prognosis in previous studies, were more common in vaccinated patients. Considerable between-country variation in both in-hospital fatality risk and vaccinated-versus-unvaccinated difference in this outcome was observed.
CONCLUSIONS
These findings will inform allocation of healthcare resources in future surges as well as design of longer-term international studies to characterize changes in clinical profile of hospitalized COVID-19 patients related to vaccination history.
FUNDING
This work was made possible by the UK Foreign, Commonwealth and Development Office and Wellcome (215091/Z/18/Z, 222410/Z/21/Z, 225288/Z/22/Z, and 220757/Z/20/Z); the Bill & Melinda Gates Foundation (OPP1209135); and the philanthropic support of the donors to the University of Oxford's COVID-19 Research Response Fund (0009109). Additional funders are listed in the "acknowledgments" section.
Topics: Humans; COVID-19; SARS-CoV-2; Hospitalization; Hospitals; Vaccination
PubMed: 37738979
DOI: 10.1016/j.medj.2023.08.005 -
Indian Pediatrics Apr 1977
Topics: Abnormalities, Multiple; Dwarfism; Female; Humans; Infant, Newborn; Lipodystrophy; Progeria; Syndrome
PubMed: 924643
DOI: No ID Found -
Journal of Pediatric Endocrinology &... Jun 2016Donohue syndrome (DS) is a rare and lethal autosomal recessive disease caused by mutations in the insulin receptor (INSR) gene, manifesting marked insulin resistance,...
Donohue syndrome (DS) is a rare and lethal autosomal recessive disease caused by mutations in the insulin receptor (INSR) gene, manifesting marked insulin resistance, severe growth retardation, hypertrichosis, and characteristic dysmorphic features. We describe a new case of Donohue syndrome born at 37 weeks' gestation of unrelated parents and presented with intra-uterine growth retardation, nipple hypertrophy, macropenis, distended abdomen, hirsutism and dysmorphic features. The clinical course showed failure to thrive, and episodes of alternating hypoglycemia and hyperglycemia. Laboratory tests revealed direct hyperbilirubinemia. The diagnosis of Donohue syndrome was established based on the above clinical characteristics and determination of the INSR mutation. He was found to have homozygous nonsense mutation c. 2270 C>T (Arg924X) at exon 14 of the INSR gene. He later developed enterocolitis and died at 3 months old. Prenatal diagnosis was performed for the family via chorionic villous biopsy. We try to explain gastrointestinal dysfunction seen in our patient.
Topics: Antigens, CD; Donohue Syndrome; Homozygote; Humans; Infant, Newborn; Male; Mutation; Receptor, Insulin
PubMed: 26974131
DOI: 10.1515/jpem-2015-0232 -
Chest Feb 2001
Topics: Acetates; Asthma; Churg-Strauss Syndrome; Cyclopropanes; Humans; Leukotriene Antagonists; Quinolines; Sulfides
PubMed: 11171764
DOI: 10.1378/chest.119.2.668 -
Clinica Chimica Acta; International... Oct 2017Donohue syndrome (DS), a rare autosomal recessive disease which represents severe insulin resistance, pre- and postnatal growth retardation, hypertrichosis, and...
Donohue syndrome (DS), a rare autosomal recessive disease which represents severe insulin resistance, pre- and postnatal growth retardation, hypertrichosis, and dysmorphic features, is caused by mutations in the insulin receptor (INSR) gene. Here, we have reported the clinical, molecular, and biochemical characterizations of a patient with DS. In this article, we have also reported a case with 2 novel INSR mutations and the DS phenotype. Using next-generation sequencing (NGS), we screened 27 known genes involved in inherited maturity-onset diabetes of the young (MODY) and identified compound heterozygous mutations in the INSR gene in the patient with DS, c.62T>G (p.L21R) and c.2563G>T (p.V855F). The positive correlation of these mutations with DS was further validated by Sanger DNA sequencing of his lineal consanguinity, indicating that these pathogenic mutations were inherited maternally and paternally, respectively. Therefore, our finding expanded the number of reported cases of this rare disease and the mutation spectrum of INSR mutation, suggesting that NGS is an accurate, rapid, and cost-effective method for the genetic diagnosis of this rare disease.
Topics: Amino Acid Sequence; Animals; Antigens, CD; Base Sequence; Child, Preschool; Donohue Syndrome; Heterozygote; Humans; Male; Molecular Dynamics Simulation; Mutation; Protein Domains; Receptor, Insulin
PubMed: 28803747
DOI: 10.1016/j.cca.2017.08.007 -
Odontology Feb 2010Rabson-Mendenhall syndrome is a rare, autosomal recessive disorder characterized by insulin resistance syndrome, growth retardation, coarse and senile-looking faces,... (Review)
Review
Rabson-Mendenhall syndrome is a rare, autosomal recessive disorder characterized by insulin resistance syndrome, growth retardation, coarse and senile-looking faces, mental precocity, early dentition, and pineal hyperplasia. Mutations of the insulin receptor gene affecting insulin action appear to be the basic mechanism underlying this syndrome. We report on Rabson-Mendenhall syndrome in two siblings and briefly review the literature.
Topics: Adolescent; Child, Preschool; Donohue Syndrome; Female; Humans; Malocclusion; Siblings; Tooth Diseases
PubMed: 20155514
DOI: 10.1007/s10266-009-0106-7 -
Zhonghua Yi Xue Yi Chuan Xue Za Zhi =... Feb 2020To explore the genetic basis for a newborn infant suspected with Donohue syndrome.
OBJECTIVE
To explore the genetic basis for a newborn infant suspected with Donohue syndrome.
METHODS
Whole exome sequencing (WES) was used to screen potential variants in the child. Suspected variants were validated through Sanger sequencing and real-time PCR.
RESULTS
The child was found to carry two heterozygous variants in the INSR gene, including c.3258+4(IVS17)A>G and deletion of exon 2, which were respectively inherited from her mother and father.
CONCLUSION
The compound heterozygous variants of the INSR gene probably underlie the disease in this patient.
Topics: Donohue Syndrome; Exons; Female; Heterozygote; Humans; Infant, Newborn; Mutation; Exome Sequencing
PubMed: 32034740
DOI: 10.3760/cma.j.issn.1003-9406.2020.02.010 -
Journal of Pediatric Endocrinology &... Nov 2022Rabson Mendenhall syndrome (RMS) is a rare form of insulin resistance syndrome caused by insulin receptor mutation. In term of severity, it lies at an intermediate...
OBJECTIVES
Rabson Mendenhall syndrome (RMS) is a rare form of insulin resistance syndrome caused by insulin receptor mutation. In term of severity, it lies at an intermediate point on spectrum of insulin resistance with Donohue syndrome flanking the severe and Type A insulin resistance at the mild end. We are reporting a 3.5-month-old boy with RMS along with its management challenges in a resource limited country.
CASE PRESENTATION
An infant presented at 3.5-month of an age with failure to thrive and fluctuating blood glucose level (hyperglycaemia and hypoglycaemia) along with clinical features of insulin resistance. He was found to have raised HbA1C, high insulin and C peptide level and a homozygous mutation in gene c.1049C>T, (p.Ser350 Leu) confirming the diagnosis of RMS. He was managed with long-acting insulin (Detemir) along with frequent feeding.
CONCLUSIONS
RMS in resource limited countries could be managed with frequent feeding along with insulin. Early diagnosis and management can improve long term outcome.
Topics: Infant; Male; Humans; Donohue Syndrome; Insulin Resistance; Receptor, Insulin; Insulin; Mutation
PubMed: 36106528
DOI: 10.1515/jpem-2022-0214