RESUMEN
Hyperinsulinemic hypoglycemia (HI) and congenital polycystic kidney disease (PKD) are rare, genetically heterogeneous disorders. The co-occurrence of these disorders (HIPKD) in 17 children from 11 unrelated families suggested an unrecognized genetic disorder. Whole-genome linkage analysis in five informative families identified a single significant locus on chromosome 16p13.2 (logarithm of odds score 6.5). Sequencing of the coding regions of all linked genes failed to identify biallelic mutations. Instead, we found in all patients a promoter mutation (c.-167G>T) in the phosphomannomutase 2 gene (PMM2), either homozygous or in trans with PMM2 coding mutations. PMM2 encodes a key enzyme in N-glycosylation. Abnormal glycosylation has been associated with PKD, and we found that deglycosylation in cultured pancreatic ß cells altered insulin secretion. Recessive coding mutations in PMM2 cause congenital disorder of glycosylation type 1a (CDG1A), a devastating multisystem disorder with prominent neurologic involvement. Yet our patients did not exhibit the typical clinical or diagnostic features of CDG1A. In vitro, the PMM2 promoter mutation associated with decreased transcriptional activity in patient kidney cells and impaired binding of the transcription factor ZNF143. In silico analysis suggested an important role of ZNF143 for the formation of a chromatin loop including PMM2 We propose that the PMM2 promoter mutation alters tissue-specific chromatin loop formation, with consequent organ-specific deficiency of PMM2 leading to the restricted phenotype of HIPKD. Our findings extend the spectrum of genetic causes for both HI and PKD and provide insights into gene regulation and PMM2 pleiotropy.
Asunto(s)
Hiperinsulinismo Congénito/complicaciones , Hiperinsulinismo Congénito/genética , Mutación , Fosfotransferasas (Fosfomutasas)/genética , Enfermedades Renales Poliquísticas/complicaciones , Enfermedades Renales Poliquísticas/genética , Regiones Promotoras Genéticas/genética , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , MasculinoRESUMEN
Congenital hearing loss is a common disorder worldwide. Heterogeneous gene variation accounts for approximately 20-25% of such patients. We investigated a five-generation Chinese family with autosomal-dominant nonsyndromic sensorineural hearing loss (SNHL). No wave was detected in the pure-tone audiometry, and the auditory brainstem response was absent in all patients. Computed tomography of the patients, as well as of two sporadic SNHL cases, showed bilateral inner ear anomaly, cochlear maldevelopment, absence of the osseous spiral lamina, and an enlarged vestibular aqueduct. Such findings were absent in nonaffected persons. We used linkage analysis and exome sequencing and uncovered a heterozygous missense mutation in the PI4KB gene (p.Gln121Arg) encoding phosphatidylinositol 4-kinase ß (PI4KB) from the patients in this family. In addition, 3 missense PI4KB (p.Val434Gly, p.Glu667Lys, and p.Met739Arg) mutations were identified in five patients with nonsyndromic SNHL from 57 sporadic cases. No such mutations were present within 600 Chinese controls, the 1000 genome project, gnomAD, or similar databases. Depleting pi4kb mRNA expression in zebrafish caused inner ear abnormalities and audiosensory impairment, mimicking the patient phenotypes. Moreover, overexpression of 4 human missense PI4KB mutant mRNAs in zebrafish embryos resulted in impaired hearing function, suggesting dominant-negative effects. Taken together, our results reveal that PI4KB mutations can cause SNHL and inner ear malformation. PI4KB should be included in neonatal deafness screening.
Asunto(s)
Predisposición Genética a la Enfermedad , Pérdida Auditiva Sensorineural/genética , Enfermedades del Laberinto/genética , Fosfotransferasas (Aceptor de Grupo Alcohol)/genética , Animales , Cóclea/patología , Oído Interno/patología , Femenino , Ligamiento Genético/genética , Pérdida Auditiva Sensorineural/patología , Humanos , Lactante , Recién Nacido , Enfermedades del Laberinto/patología , Masculino , Mutación Missense/genética , Fenotipo , Polimorfismo de Nucleótido Simple/genética , Secuenciación del Exoma , Pez Cebra/genéticaRESUMEN
BACKGROUND: The heterotrimeric GTP-binding protein eIF2 forms a ternary complex with initiator methionyl-tRNA and recruits it to the 40S ribosomal subunit for start codon selection and thereby initiates protein synthesis. Mutations in EIF2S3, encoding the eIF2γ subunit, are associated with severe intellectual disability and microcephaly, usually as part of MEHMO syndrome. METHODS: Exome sequencing of the X chromosome was performed on three related males with normal head circumferences and mild learning difficulties, hypopituitarism (GH and TSH deficiencies), and an unusual form of glucose dysregulation. In situ hybridisation on human embryonic tissue, EIF2S3-knockdown studies in a human pancreatic cell line, and yeast assays on the mutated corresponding eIF2γ protein, were performed in this study. FINDINGS: We report a novel hemizygous EIF2S3 variant, p.Pro432Ser, in the three boys (heterozygous in their mothers). EIF2S3 expression was detectable in the developing pituitary gland and pancreatic islets of Langerhans. Cells lacking EIF2S3 had increased caspase activity/cell death. Impaired protein synthesis and relaxed start codon selection stringency was observed in mutated yeast. INTERPRETATION: Our data suggest that the p.Pro432Ser mutation impairs eIF2γ function leading to a relatively mild novel phenotype compared with previous EIF2S3 mutations. Our studies support a critical role for EIF2S3 in human hypothalamo-pituitary development and function, and glucose regulation, expanding the range of phenotypes associated with EIF2S3 mutations beyond classical MEHMO syndrome. Untreated hypoglycaemia in previous cases may have contributed to their more severe neurological impairment and seizures in association with impaired EIF2S3. FUND: GOSH, MRF, BRC, MRC/Wellcome Trust and NIGMS funded this study.
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Factor 2 Eucariótico de Iniciación/genética , Genes Ligados a X , Glucosa/metabolismo , Hipopituitarismo/etiología , Hipopituitarismo/metabolismo , Fenotipo , Sustitución de Aminoácidos , Apoptosis , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Línea Celular , Preescolar , Factor 2 Eucariótico de Iniciación/química , Factor 2 Eucariótico de Iniciación/metabolismo , Técnicas de Silenciamiento del Gen , Humanos , Hipopituitarismo/diagnóstico , Hibridación in Situ , Lactante , Imagen por Resonancia Magnética , Mutación , Linaje , Polimorfismo de Nucleótido Simple , Biosíntesis de ProteínasRESUMEN
Pancreatic ß cells are functionally programmed to release insulin in response to changes in plasma glucose concentration. Insulin secretion is precisely regulated so that, under normal physiological conditions, fasting plasma glucose concentrations are kept within a narrow range of 3·5-5·5 mmol/L. In hyperinsulinaemic hypoglycaemia, insulin secretion becomes dysregulated (ie, uncoupled from glucose metabolism) so that insulin secretion persists in the presence of low plasma glucose concentrations. Hyperinsulinaemic hypoglycaemia is the most common cause of severe and persistent hypoglycaemia in neonates and children. At a molecular level, mutations in nine different genes can lead to the dysregulation of insulin secretion and cause this disorder. In adults, hyperinsulinaemic hypoglycaemia accounts for 0·5-5·0% of cases of hypoglycaemia and can be due either to ß-cell tumours (insulinomas) or ß-cell hyperplasia. Rapid diagnosis and prompt management of hyperinsulinaemic hypoglycaemia is essential to avoid hypoglycaemic brain injury, especially in the vulnerable neonatal and childhood periods. Advances in the field of hyperinsulinaemic hypoglycaemia include use of rapid molecular genetic testing for the disease, application of novel imaging techniques (6-[fluoride-18]fluoro-levodopa [18F-DOPA] PET-CT and glucagon-like peptide 1 (GLP-1) receptor imaging), and development of novel medical treatments (eg, long-acting octreotide formulations, mTOR inhibitors, and GLP-1 receptor antagonists) and surgical therapies (eg, laparoscopic surgery).
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Hiperinsulinismo , Hipoglucemia , Adolescente , Niño , Glucosa/metabolismo , Humanos , Hiperinsulinismo/diagnóstico , Hiperinsulinismo/etiología , Hiperinsulinismo/terapia , Hipoglucemia/diagnóstico , Hipoglucemia/etiología , Hipoglucemia/terapia , Hipoglucemiantes/uso terapéutico , Células Secretoras de Insulina/metabolismoRESUMEN
Glucose homeostasis requires appropriate and synchronous coordination of metabolic events and hormonal activities to keep plasma glucose concentrations in a narrow range of 3.5-5.5 mmol/L. Insulin, the only glucose lowering hormone secreted from pancreatic ß-cells, plays the key role in glucose homeostasis. Insulin release from pancreatic ß-cells is mainly regulated by intracellular ATP-generating metabolic pathways. Hyperinsulinaemic hypoglycaemia (HH), the most common cause of severe and persistent hypoglycaemia in neonates and children, is the inappropriate secretion of insulin which occurs despite low plasma glucose levels leading to severe and persistent hypoketotic hypoglycaemia. Mutations in 12 different key genes (ABCC8, KCNJ11, GLUD1, GCK, HADH, SLC16A1, UCP2, HNF4A, HNF1A, HK1, PGM1 and PMM2) constitute the underlying molecular mechanisms of congenital HH. Since insulin supressess ketogenesis, the alternative energy source to the brain, a prompt diagnosis and immediate management of HH is essential to avoid irreversible hypoglycaemic brain damage in children. Advances in molecular genetics, imaging methods (18F-DOPA PET-CT), medical therapy and surgical approach (laparoscopic and open pancreatectomy) have changed the management and improved the outcome of patients with HH. This up to date review article provides a background to the diagnosis, molecular genetics, recent advances and therapeutic options in the field of HH in children.
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The obesity epidemic is a significant global health issue. Improved understanding of the mechanisms that regulate appetite and body weight will provide the rationale for the design of anti-obesity therapies. Thyroid hormones play a key role in metabolic homeostasis through their interaction with thyroid hormone receptors (TRs), which function as ligand-inducible transcription factors. The TR-beta isoform (TRß) is expressed in the ventromedial hypothalamus (VMH), a brain area important for control of energy homeostasis. Here, we report that selective knockdown of TRß in the VMH of adult mice results in severe obesity due to hyperphagia and reduced energy expenditure. The observed increase in body weight is of a similar magnitude to murine models of the most extreme forms of monogenic obesity. These data identify TRß in the VMH as a major physiological regulator of food intake and energy homeostasis.
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Peso Corporal/genética , Ingestión de Alimentos/genética , Receptores beta de Hormona Tiroidea/metabolismo , Núcleo Hipotalámico Ventromedial/metabolismo , Animales , Peso Corporal/fisiología , Masculino , RatonesRESUMEN
Glucose is the key metabolic substrate for tissue energy production. In the perinatal period the mother supplies glucose to the fetus and for most of the gestational period the normal lower limit of fetal glucose concentration is around 3â mmol/L. Just after birth, for the first few hours of life in a normal term neonate appropriate for gestational age, blood glucose levels can range between 1.4 mmol/L and 6.2â mmol/L but by about 72â h of age fasting blood glucose levels reach normal infant, child and adult values (3.5-5.5â mmol/L). Normal blood glucose levels are maintained within this narrow range by factors which control glucose production and glucose utilisation. The key hormones which regulate glucose homoeostasis include insulin, glucagon, epinephrine, norepinephrine, cortisol and growth hormone. Pathological states that affect either glucose production or utilisation will lead to hypoglycaemia. Although hypoglycaemia is a common biochemical finding in children (especially in the newborn) it is not possible to define by a single (or a range of) blood glucose value/s. It can be defined as the concentration of glucose in the blood or plasma at which the individual demonstrates a unique response to the abnormal milieu caused by the inadequate delivery of glucose to a target organ (eg, the brain). Hypoglycaemia should therefore be considered as a continuum and the blood glucose level should be interpreted within the clinical scenario and with respect to the counter-regulatory hormonal responses and intermediate metabolites.
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Glucemia/metabolismo , Adolescente , Adulto , Lactancia Materna , Niño , Preescolar , Ingestión de Alimentos/fisiología , Metabolismo Energético/fisiología , Ayuno/sangre , Femenino , Feto/química , Transportador de Glucosa de Tipo 1/fisiología , Glucógeno/metabolismo , Hormonas/metabolismo , Humanos , Hipoglucemia/sangre , Hipoglucemia/diagnóstico , Lactante , Recién Nacido , Intercambio Materno-Fetal/fisiología , EmbarazoRESUMEN
Under normal physiological conditions, pancreatic ß-cells secrete insulin to maintain fasting blood glucose levels in the range 3.5-5.5 mmol/L. In hyperinsulinemic hypoglycemia (HH), this precise regulation of insulin secretion is perturbed so that insulin continues to be secreted in the presence of hypoglycemia. HH may be due to genetic causes (congenital) or secondary to certain risk factors. The molecular mechanisms leading to HH involve defects in the key genes regulating insulin secretion from the ß-cells. At this moment, in time genetic abnormalities in nine genes (ABCC8, KCNJ11, GCK, SCHAD, GLUD1, SLC16A1, HNF1A, HNF4A, and UCP2) have been described that lead to the congenital forms of HH. Perinatal stress, intrauterine growth retardation, maternal diabetes mellitus, and a large number of developmental syndromes are also associated with HH in the neonatal period. In older children and adult's insulinoma, non-insulinoma pancreatogenous hypoglycemia syndrome and post bariatric surgery are recognized causes of HH. This review article will focus mainly on describing the molecular mechanisms that lead to unregulated insulin secretion.
RESUMEN
BACKGROUND: Alström syndrome (AS) is an extremely rare, autosomal recessive disorder characterised by multi-organ features that typically manifest within the first two decades of life. AS is caused by mutations in the Alström syndrome 1 (ALMS1) gene located at 2p13.1. METHODS: In the current study, two brothers from a first-cousin consanguineous family presented with a complex phenotype and were suspected of having AS. RESULTS: Both brothers were found to be homozygous for a novel nonsense c.7310C>A (p.S2437X) mutation in exon-8 of ALMS1 gene. The consanguineous parents were sequenced and both were heterozygous for the same mutation. CONCLUSIONS: This particular mutation has never been reported before and confirmed the diagnosis of AS in the patients. Our work identifies a novel mutation in ALMS1 gene responsible for the complex phenotype of AS in these patients.
Asunto(s)
Síndrome de Alstrom/genética , Mutación/genética , Proteínas/genética , Adolescente , Adulto , Síndrome de Alstrom/patología , Proteínas de Ciclo Celular , Niño , Consanguinidad , Femenino , Heterocigoto , Homocigoto , Humanos , Masculino , Linaje , Fenotipo , Pronóstico , Hermanos , Turquía , Adulto JovenRESUMEN
Congenital hyperinsulinism (CHI) is a complex heterogeneous condition in which insulin secretion from pancreatic ß-cells is unregulated and inappropriate for the level of blood glucose. The inappropriate insulin secretion drives glucose into the insulin-sensitive tissues, such as the muscle, liver and adipose tissue, leading to severe hyperinsulinaemic hypoglycaemia (HH). At a molecular level, genetic abnormalities in nine different genes (ABCC8, KCNJ11, GLUD1, GCK, HNF4A, HNF1A, SLC16A1, UCP2 and HADH) have been identified which cause CHI. Autosomal recessive and dominant mutations in ABCC8/KCNJ11 are the commonest cause of medically unresponsive CHI. Mutations in GLUD1 and HADH lead to leucine-induced HH, and these two genes encode the key enzymes glutamate dehydrogenase and short chain 3-hydroxyacyl-CoA dehydrogenase which play a key role in amino acid and fatty acid regulation of insulin secretion respectively. Genetic abnormalities in HNF4A and HNF1A lead to a dual phenotype of HH in the newborn period and maturity onset-diabetes later in life. This state of the art review provides an update on the molecular basis of CHI.
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Hiperinsulinismo Congénito/genética , Animales , Hiperinsulinismo Congénito/patología , Humanos , Insulina/metabolismo , Secreción de Insulina , Modelos BiológicosRESUMEN
Congenital hyperinsulinism (CHI) is caused by unregulated insulin release and leads to hyperinsulinaemic-hypoglycaemia (HH). Glucagon like peptide-1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), peptide YY (PYY) and the enzyme; dipeptidyl peptidase-4 (DPP-4) all regulate appetite and glucose homeostasis. These proteins have been identified as possible contributors to HH but the mechanism remains poorly understood. We aimed to look at the expression pattern of pancreatic DPP-4 in children with focal and diffuse CHI (FCHI and DCHI, respectively). Using immunohistochemistry; we determined DPP-4 expression patterns in the pancreas of CHI patients. DPP-4 was found to be expressed in the pancreatic ß, α and δ-cells in and around the focal area. However, it was predominantly co-localised with ß-cells in the paediatric tissue samples. Additionally, proliferating ß-cells expressed DPP-4 in DCHI, which was absent in the FCHI pancreas. Insulin was found to be present in the exocrine acini and duct cells of the DCHI pancreas suggestive of exocrine to endocrine transdifferentiation. Furthermore, 6 medically-unresponsive DCHI pancreatic samples showed an up-regulation of total pancreatic DPP-4 expression. In conclusion; the expression studies have shown DPP-4 to be altered in HH, however, further work is required to understand the underlying role for this enzyme.
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Hiperinsulinismo Congénito/enzimología , Dipeptidil Peptidasa 4/análisis , Páncreas/enzimología , Adulto , Biomarcadores/análisis , Estudios de Casos y Controles , Proliferación Celular , Transdiferenciación Celular , Hiperinsulinismo Congénito/genética , Hiperinsulinismo Congénito/patología , Hiperinsulinismo Congénito/cirugía , Dipeptidil Peptidasa 4/genética , Femenino , Perfilación de la Expresión Génica/métodos , Humanos , Inmunohistoquímica , Lactante , Células Secretoras de Insulina/enzimología , Masculino , Análisis de Secuencia por Matrices de Oligonucleótidos , Páncreas/patología , Páncreas/cirugía , Regulación hacia ArribaRESUMEN
Congenital hyperinsulinism (CHI) is a common cause of hypoglycaemia due to unregulated insulin secretion from pancreatic ß cells. Medical management includes use of oral diazoxide (a KATP channel agonist) and daily injectable octreotide (somatostatin analogue) therapy. However, diazoxide is associated with severe sideeffects such as coarse facies, hypertrichosis and psychosocial/compliance issues in adolescents. Lanreotide (a long-acting somatostatin analogue) is used in adults with neuroendocrine tumours; however, its role in patients with CHI has not been well described. A 15-year-old girl with diazoxide-responsive CHI had severe hypertrichosis secondary to diazoxide and subsequent compliance/psychosocial issues. She was commenced on 30 mg of lanreotide every 4 weeks as a deep subcutaneous injection, in an attempt to address these issues. She was able to come off diazoxide treatment 2 months after starting lanreotide. Presently, after 2.5 years of lanreotide treatment, her blood glucose control is stable with complete resolution of hypertrichosis. Clinically significant improvements in the self-reported Paediatric Quality of Life (PedsQL) questionnaire and Strengths and Difficulties Questionnaire (SDQ) were reported after 1 year on lanreotide. No side effects were found, and her liver/thyroid function and abdominal ultrasound have been normal. We report the first case on the use of lanreotide in an adolescent girl with diazoxide-responsive CHI with significant improvement of quality of life.