scholarly journals Metabolic disturbances of the vitamin A pathway in human diaphragmatic hernia

2015 ◽  
Vol 308 (2) ◽  
pp. L147-L157 ◽  
Author(s):  
Karen Coste ◽  
Leonardus W. J. E. Beurskens ◽  
Pierre Blanc ◽  
Denis Gallot ◽  
Amélie Delabaere ◽  
...  
Keyword(s):  
Diaphragmatic Hernia ◽  
Perinatal Death ◽  
Single Gene ◽  
Gene Mutations ◽  
Transcriptional Analysis ◽  
Metabolic Disturbances ◽  
Common Life ◽  
Retinoid Signaling ◽  
Life Threatening ◽  
Surgically Induced

Congenital diaphragmatic hernia (CDH) is a common life-threatening congenital anomaly resulting in high rates of perinatal death and neonatal respiratory distress. Some of the nonisolated forms are related to single-gene mutations or genomic rearrangements, but the genetics of the isolated forms (60% of cases) still remains a challenging issue. Retinoid signaling (RA) is critical for both diaphragm and lung development, and it has been hypothesized that subtle disruptions of this pathway could contribute to isolated CDH etiology. Here we used time series of normal and CDH lungs in humans, in nitrofen-exposed rats, and in surgically induced hernia in rabbits to perform a systematic transcriptional analysis of the RA pathway key components. The results point to CRPBP2, CY26B1, and ALDH1A2 as deregulated RA signaling genes in human CDH. Furthermore, the expression profile comparisons suggest that ALDH1A2 overexpression is not a primary event, but rather a consequence of the CDH-induced lung injury. Taken together, these data show that RA signaling disruption is part of CDH pathogenesis, and also that dysregulation of this pathway should be considered organ specifically.

Early-onset severe obesity due to complete deletion of the leptin gene in a boy

2017 ◽  
Vol 30 (11) ◽  
Author(s):  
Elif Ozsu ◽  
Serdar Ceylaner ◽  
Huseyin Onay
Keyword(s):  
Early Onset ◽  
Severe Obesity ◽  
Food Addiction ◽  
Single Gene ◽  
Gene Mutations ◽  
Metabolic Disturbances ◽  
Case Presentation ◽  
Monogenic Obesity ◽  
Abnormal Rate ◽  
Normal Body Weight

AbstractBackground:Monogenic obesity results from single gene mutations. Extreme obesity starting at an early age, especially in infancy, which is associated with endocrinopathy and metabolic disturbances is key to the diagnosis of monogenic obesity.Case presentation:A 6-month-old boy was admitted to our clinic with severe obesity and food craving. He was born with a birth weight of 3400 g to first-cousin parents. He started to gain weight at an abnormal rate at the age of 2 months. He had hyperinsulinemia, dyslipidemia and grade 2 hepatosteatosis. He had a 7-year-old, healthy brother with a normal body weight. Because of severe early-onset obesity and abnormal food addiction, his leptin level was measured and found to be 0.55 ng/mL (normal range for his age and sex is 0.7–21 ng/mL). AConclusions:To the best of our knowledge, a gross deletion of the

Sexual Differentiation

2011 ◽  
Author(s):  
Michael J. Mcphaul ◽  
Richard J. Auchus
Keyword(s):  
Y Chromosome ◽  
Sexual Development ◽  
Sexual Differentiation ◽  
Single Gene ◽  
Gene Mutations ◽  
Testicular Descent ◽  
Disorders Of Sexual Development ◽  
Sexual Characteristics ◽  
Life Threatening ◽  
Disorders Of Sexual Differentiation

Sexual differentiation is a sequential process that begins at fertilization with the establishment of chromosomal sex, continues with the determination of gonadal sex, and culminates in the development of secondary sexual characteristics that comprise the male and female phenotypes. This basic paradigm was formulated by Alfred Jost to explain the results of castration experiments in fetal rabbits. If the gonads (ovaries or testes) were removed before sexual differentiation, female sexual differentiation inevitably ensued. The male pathway could be partly restored by testosterone implants, suggesting that hormones produced by the testes mediate male sexual development. Thus, the concept arose that the testes induce a male pattern of differentiation on an embryo that otherwise would follow the female pathway. Cytogenetic studies shortly thereafter showed that the critical genetic determinant of sex is the presence or absence of the Y chromosome, leading to the proposal that the Y chromosome directs the gonad to differentiate into a testis, which then produces hormone(s) that cause male sexual differentiation. The chromosomal sex of the embryo generally corresponds to its phenotypic sex. Occasionally, however, the process of sexual differentiation goes awry, resulting in individuals with disorders of sexual differentiation (DSD). Clinically recognized disorders of sexual development occur at many levels, ranging from relatively common disorders in the terminal steps of male differentiation (e.g., testicular descent, growth of the penis) to more fundamental abnormalities that lead to varying degrees of ambiguity of phenotypic sex. Although most of these abnormalities impair reproduction, they usually are not life threatening. Thus, humans and experimental animals with naturally occurring defects in sexual differentiation survive to reach the attention of physicians and scientists. This chapter reviews the sequence of events in normal sexual development and describes disorders of this process — many of which result from single-gene mutations — that have provided valuable insights into the mechanisms of sexual differentiation. Normally, human somatic cells have 22 pairs of autosomes and 1 pair of sex chromosomes.

scholarly journals The OSMR Gene Is Involved in Hirschsprung Associated Enterocolitis Susceptibility through an Altered Downstream Signaling

2021 ◽  
Vol 22 (8) ◽  
pp. 3831
Author(s):  
Tiziana Bachetti ◽  
Francesca Rosamilia ◽  
Martina Bartolucci ◽  
Giuseppe Santamaria ◽  
Manuela Mosconi ◽  
...  
Keyword(s):  
Immune Response ◽  
Oncostatin M ◽  
Common Life ◽  
Downstream Signaling ◽  
Whole Exome ◽  
Gut Homeostasis ◽  
Life Threatening ◽  
Infection And Inflammation ◽  
Susceptibility Variant ◽  
Oncostatin M Receptor

Hirschsprung (HSCR) Associated Enterocolitis (HAEC) is a common life-threatening complication in HSCR. HAEC is suggested to be due to a loss of gut homeostasis caused by impairment of immune system, barrier defense, and microbiome, likely related to genetic causes. No gene has been claimed to contribute to HAEC occurrence, yet. Genetic investigation of HAEC by Whole-Exome Sequencing (WES) on 24 HSCR patients affected (HAEC) or not affected (HSCR-only) by enterocolitis and replication of results on a larger panel of patients allowed the identification of the HAEC susceptibility variant p.H187Q in the Oncostatin-M receptor (OSMR) gene (14.6% in HAEC and 5.1% in HSCR-only, p = 0.0024). Proteomic analysis on the lymphoblastoid cell lines from one HAEC patient homozygote for this variant and one HAEC patient not carrying the variant revealed two well distinct clusters of proteins significantly up or downregulated upon OSM stimulation. A marked enrichment in immune response pathways (q < 0.0001) was shown in the HAEC H187 cell line, while proteins upregulated in the HAEC Q187 lymphoblasts sustained pathways likely involved in pathogen infection and inflammation. In conclusion, OSMR p.H187Q is an HAEC susceptibility variant and perturbates the downstream signaling cascade necessary for the gut immune response and homeostasis maintenance.

Diaphragmatic Hernia

1983 ◽  
Vol 4 (8) ◽  
pp. 244-266
Keyword(s):  
Intensive Care ◽  
Pulmonary Arterial Hypertension ◽  
Diaphragmatic Hernia ◽  
Neonatal Intensive Care ◽  
Pulmonary Hypoplasia ◽  
Thoracic Cavity ◽  
Hemodynamic Changes ◽  
Life Threatening ◽  
Pulmonary Arterial ◽  
Immediate Surgery

In spite of the availability of almost immediate surgery and neonatal intensive care, congenital diaphragmatic hernia is a life-threatening anomaly in the newborn. It is the result of early embryologic malformation or failure of fusion of the components of the diaphragm allowing for the displacement of the abdominal contents into the thoracic cavity. There is consequent compression of the lung which may result in pulmonary hypoplasia or compression of the cardiovascular structures resulting in deleterious hemodynamic changes. Hypoxia and acidosis result in the presentation of respiratory distress and cyanosis. This is frequently associated with pulmonary arterial hypertension with right to left shunting through fetal circuits.

scholarly journals Whole-exome sequencing associates novel CSMD1 gene mutations with familial Parkinson disease

2017 ◽  
Vol 3 (5) ◽  
pp. e177 ◽  
Author(s):  
Javier Ruiz-Martínez ◽  
Luis J. Azcona ◽  
Alberto Bergareche ◽  
Jose F. Martí-Massó ◽  
Coro Paisán-Ruiz
Keyword(s):  
Parkinson Disease ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Genome Wide Association Study ◽  
Single Gene ◽  
Gene Mutations ◽  
Complement Control Protein ◽  
Genome Wide ◽  
Whole Exome ◽  
A Genome

Objective:Despite the enormous advancements made in deciphering the genetic architecture of Parkinson disease (PD), the majority of PD is idiopathic, with single gene mutations explaining only a small proportion of the cases.Methods:In this study, we clinically evaluated 2 unrelated Spanish families diagnosed with PD, in which known PD genes were previously excluded, and performed whole-exome sequencing analyses in affected individuals for disease gene identification.Results:Patients were diagnosed with typical PD without relevant distinctive symptoms. Two different novel mutations were identified in the CSMD1 gene. The CSMD1 gene, which encodes a complement control protein that is known to participate in the complement activation and inflammation in the developing CNS, was previously shown to be associated with the risk of PD in a genome-wide association study.Conclusions:We conclude that the CSMD1 mutations identified in this study might be responsible for the PD phenotype observed in our examined patients. This, along with previous reported studies, may suggest the complement pathway as an important therapeutic target for PD and other neurodegenerative diseases.

scholarly journals Jervell and Lange-Nielsen Syndrome due to a Novel Compound Heterozygous KCNQ1 Mutation in a Chinese Family

2020 ◽  
Vol 2020 ◽  
pp. 1-8
Author(s):  
Yue Qiu ◽  
Sen Chen ◽  
Xia Wu ◽  
Wen-Juan Zhang ◽  
Wen Xie ◽  
...  
Keyword(s):  
Deaf Child ◽  
Gene Mutations ◽  
Deaf Children ◽  
Chinese Family ◽  
Compound Heterozygous ◽  
Qtc Interval ◽  
Cardiac Events ◽  
Life Threatening ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing

Jervell and Lange-Nielsen syndrome (JLNS) is a rare but severe autosomal recessive disease characterized by profound congenital deafness and a prolonged QTc interval (greater than 500 milliseconds) in the ECG waveforms. The prevalence of JLNS is about 1/1000000 to 1/200000 around the world. However, exceed 25% of JLNS patients suffered sudden cardiac death with kinds of triggers containing anesthesia. Approximately 90% of JLNS cases are caused by KCNQ1 gene mutations. Here, using next-generation sequencing (NGS), we identified a compound heterozygosity for two mutations c.1741A>T (novel) and c.477+5G>A (known) in KCNQ1 gene as the possible pathogenic cause of JLNS, which suggested a high risk of cardiac events in a deaf child. The hearing of this patient improved significantly with the help of cochlear implantation (CI). But life-threatening arrhythmias occurred with a trigger of anesthesia after the end of the CI surgery. Our findings extend the KCNQ1 gene mutation spectrum and contribute to the management of deaf children diagnosed with JLNS for otolaryngologists (especially cochlear implant teams).

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