scholarly journals Congenital Leptin Deficiency and Leptin Gene Missense Mutation Found in Two Colombian Sisters with Severe Obesity

Genes ◽  
2019 ◽  
Vol 10 (5) ◽  
pp. 342 ◽  
Author(s):  
Hernan Yupanqui-Lozno ◽  
Raul A. Bastarrachea ◽  
Maria E. Yupanqui-Velazco ◽  
Monica Alvarez-Jaramillo ◽  
Esteban Medina-Méndez ◽  
...  
Keyword(s):  
Missense Mutation ◽  
Severe Obesity ◽  
Direct Sequencing ◽  
Genetic Disorder ◽  
Protein Product ◽  
Coding Region ◽  
Rare Type ◽  
Serum Leptin ◽  
Leptin Deficiency ◽  
Lep Gene

Background: Congenital leptin deficiency is a recessive genetic disorder associated with severe early-onset obesity. It is caused by mutations in the leptin (LEP) gene, which encodes the protein product leptin. These mutations may cause nonsense-mediated mRNA decay, defective secretion or the phenomenon of biologically inactive leptin, but typically lead to an absence of circulating leptin, resulting in a rare type of monogenic extreme obesity with intense hyperphagia, and serious metabolic abnormalities. Methods: We present two severely obese sisters from Colombia, members of the same lineal consanguinity. Their serum leptin was measured by MicroELISA. DNA sequencing was performed on MiSeq equipment (Illumina) of a next-generation sequencing (NGS) panel involving genes related to severe obesity, including LEP. Results: Direct sequencing of the coding region of LEP gene in the sisters revealed a novel homozygous missense mutation in exon 3 [NM_002303.3], C350G>T [p.C117F]. Detailed information and clinical measurements of these sisters were also collected. Their serum leptin levels were undetectable despite their markedly elevated fat mass. Conclusions: The mutation of LEP, absence of detectable leptin, and the severe obesity found in these sisters provide the first evidence of monogenic leptin deficiency reported in the continents of North and South America.

scholarly journals A Novel Homozygous Frameshift Mutation in Exon 2 of LEP Gene Associated with Severe Obesity: A Case Report

2016 ◽  
Vol 10 ◽  
pp. CMPed.S40432 ◽  
Author(s):  
Ashwaq Shukri Altawil ◽  
Horia Ahmad Mawlawi ◽  
Khalid Ateeq Alghamdi ◽  
Faten Fohaid Almijmaj
Keyword(s):  
Frameshift Mutation ◽  
Sequence Data ◽  
Direct Sequencing ◽  
Single Gene ◽  
Demographic Data ◽  
Normal Vaginal Delivery ◽  
Rare Type ◽  
Exon 2 ◽  
Monogenic Obesity ◽  
Lep Gene

Background Monogenic obesity is a rare type of obesity caused by a mutation in a single gene. Patients with monogenic obesity may develop early onset of obesity and severe metabolic abnormalities. Case Presentation A two-and-half-year-old girl was presented to our clinic because of excessive weight gain and hyperphagia. She was born at full term, by normal vaginal delivery with birth weight of 2.82 kg and no complications during pregnancy. The patient was the second child of two healthy, non-obese Saudis with known consanguinity. She gained weight rapidly leading to obesity at the age of three months. Methods The demographic data and clinical features were recorded. Blood samples were collected and tested for endocrine and metabolic characteristics and genetic studies. Mutations of the LEP gene were screened. The coding exons 2 and 3 and the corresponding exon–intron boundaries were amplified by polymerase chain reaction using specific primers, analyzed by direct sequencing using an ABI sequencer 3500 xL GA (Applied Biosystems), and evaluated using the JSI SeqPilot software. The resulting sequence data were compared with the reference MM_0002302. Conclusion We report a novel homozygous frameshift mutation c.144delin TAC (G1n49Thrfs*23) in exon 2 of the LEP gene associated with extreme obesity.

Lack of effects of circulating thyroid hormone levels on serum leptin concentrations

1997 ◽  
pp. 659-663 ◽  
Author(s):  
S Corbetta ◽  
P Englaro ◽  
S Giambona ◽  
L Persani ◽  
WF Blum ◽  
...  
Keyword(s):  
Thyroid Hormones ◽  
Standard Deviation Score ◽  
Protein Product ◽  
Primary Hypothyroidism ◽  
Central Hypothyroidism ◽  
Serum Leptin ◽  
Thyroxine Therapy ◽  
Significant Difference ◽  
Before And After ◽  
Thyroxine Replacement Therapy

Leptin is the protein product of the ob gene, secreted by adipocytes. It has been suggested that it may play an important role in regulating appetite and energy expenditure. The aim of this study was to evaluate a possible interaction of thyroid hormones with the leptin system. We studied 114 adult patients (65 females and 49 males): 36 were affected with primary hypothyroidism (PH), 38 with central hypothyroidism (CH) and 40 with thyrotoxicosis (TT). Patients with CH were studied both before and after 6 months of L-thyroxine replacement therapy. Body mass index (BMI; kg/m2), thyroid function and fasting serum leptin were assessed in all patients. Since BMI has been proved to be the major influencing variable of circulating leptin levels, data were expressed as standard deviation score (SDS) calculated from 393 male and 561 female controls matched for age and BMI. No difference in SDS was recorded between males and females whatever the levels of circulating thyroid hormones. In males, no significant difference was recorded among the SDSs of PH (-0.36 +/- 1.2), TT (-0.35 +/- 1.2) and CH (0.01 +/- 1.4) patients. Females with PH had an SDSs significantly lower than TT females (-0.77 +/- 1.0 vs -0.06 +/- 1.2; P < 0.02), while no significant differences between CH (-0.34 +/- 0.7) and TT females or between CH and PH females were observed. SDS in CH patients after 6 months of L-thyroxine therapy significantly varied only in females (0.25 +/- 1.4). In conclusion, circulating thyroid hormones do not appear to play any relevant role in leptin synthesis and secretion. However, as females with either overt hypo- or hyper-thyroidism or central hypothyroidism after L-thyroxine therapy show differences in their SDSs, a subtle interaction between sex steroids and thyroid status in modulating leptin secretion, at least in women, may occur.

scholarly journals Identification of Glycoprotein gpTRL10 as a Structural Component of Human Cytomegalovirus

2002 ◽  
Vol 76 (3) ◽  
pp. 1450-1460 ◽  
Author(s):  
S. Spaderna ◽  
H. Blessing ◽  
E. Bogner ◽  
W. Britt ◽  
M. Mach
Keyword(s):  
Human Cytomegalovirus ◽  
Structural Component ◽  
Laboratory Strain ◽  
Immunoblot Analysis ◽  
Protein Product ◽  
Clinical Isolates ◽  
Coding Region ◽  
Reading Frame ◽  
Infected Cells ◽  
Strain Ad169

ABSTRACT Human cytomegalovirus (HCMV) has a coding capacity for glycoproteins which far exceeds that of other herpesviruses. Few of these proteins have been characterized. We have investigated the gene product(s) of reading frame 10, which is present in both the internal and terminal repeat regions of HCMV strain AD169 and only once in clinical isolates. The putative protein product is a 171-amino-acid glycoprotein with a theoretical mass of 20.5 kDa. We characterized the protein encoded by this reading frame in the laboratory strain AD169 and a recent isolate, TB40E. The results from both strains were comparable. Northern blot analyses showed that the gene was transcribed with early/late kinetics. Two proteins of 22 and 23.5-kDa were detected in virus-infected cells and in cells transiently expressing recombinant TRL10. Both forms contained only high-mannose-linked carbohydrate modifications. In addition, virus-infected cells expressed small amounts of the protein modified with complex N-linked sugars. Image analysis localized transiently expressed TRL10 to the endoplasmic reticulum. Immunoblot analyses as well as immunoelectron microscopy of purified virions demonstrated that TRL10 represents a structural component of the virus particle. Immunoblot analysis in the absence of reducing agents indicated that TRL10, like the other HCMV envelope glycoproteins, is present in a disulfide-linked complex. Sequence analysis of the TRL10 coding region in nine low-passage clinical isolates revealed strain-specific variation. In summary, the protein product of the TRL10 open reading frame represents a novel structural glycoprotein of HCMV and was termed gpTRL10.

Sequence Length of HIV-1 Subtype B Increases Over Time: Analyzing a Cohort of Patients with Hemophilia Over 30 Years

2021 ◽  
Author(s):  
Young-Keol Cho ◽  
Jung-eun Kim ◽  
Brian Foley
Keyword(s):  
Direct Sequencing ◽  
National Laboratory ◽  
Sequence Length ◽  
Coding Region ◽  
Los Alamos National Laboratory ◽  
Subtype B ◽  
Combined Antiretroviral Therapy ◽  
Signature Pattern ◽  
Hiv 1 ◽  
Over Time

The objective of this study is to investigate whether the sequence length of HIV-1 increases over time. A longitudinal analysis of full-length coding region sequences (FLs) in an outbreak of HIV-1 infection among patients with hemophilia and local controls identified as infected with the Korean subclade B of HIV-1 (KSB). Genes amplified by overlapping RT-PCR or nested PCR were subjected to direct sequencing. In total, 141 FLs were sequentially determined over 30 years in 62 KSB-infected patients. Non-KSB sequences were retrieved from the Los Alamos National Laboratory HIV Database. Phylogenetic analysis indicated that within KSB, 2 FLs from plasma donors O and P comprised two clusters together with 8 and 12 patients with hemophilia, respectively. Signature pattern analysis for the KSB of HIV-1 revealed signature nucleotide residues at 1.05%, compared with local controls. Additionally, in-depth FLs sequence analysis over 30 years in KSB indicates that the KSB FL significantly increases over time before combined antiretroviral therapy (cART) and decreases on cART. Furthermore, the increase in FLs over time significantly occurred in the subtypes B, C and G, but, there was no increase in the subtypes D, A, and F1. Consequently, subtypes F1 and D had the shortest sequence length. Our analysis was extended to compare HIV-1 with HIV-2 and SIVs. Essentially, the longer the sequence length (SIVsm &gt; HIV-2 &gt; SIVcpz &gt; HIV-1), the longer the survival period. The increase in the length of the HIV-1 sequence over time suggests that it might be an evolutionary direction toward attenuated pathogenicity.

scholarly journals Mutational analysis of the CDKN2 (MTS1/p16ink4A) gene in primary B-cell lymphomas

Blood ◽  
1995 ◽  
Vol 86 (7) ◽  
pp. 2724-2731 ◽  
Author(s):  
T Uchida ◽  
T Watanabe ◽  
T Kinoshita ◽  
T Murate ◽  
H Saito ◽  
...  
Keyword(s):  
B Cell ◽  
Missense Mutation ◽  
Southern Blot ◽  
Blot Analysis ◽  
Southern Blot Analysis ◽  
Mutational Analysis ◽  
Direct Sequencing ◽  
Lymphocytic Leukemia ◽  
Sscp Analysis ◽  
Putative Tumor Suppressor Gene

Abstract The CDKN2 gene located on chromosome 9p21 encodes the cyclin-dependent kinase-4 inhibitor p16. This gene is a putative tumor-suppressor gene because of its frequent alterations in many kinds of tumor cell lines. We analyzed the CDKN2 gene to evaluate its alterations in 52 primary specimens of non-Hodgkin's lymphoma (NHL) or chronic lymphocytic leukemia (CLL) of B-cell origin by Southern blot analysis, polymerase chain reaction-mediated single-strand conformation polymorphism (PCR-SSCP) analysis, and direct sequencing. By Southern blot analysis, we showed homozygous deletion of the CDKN2 gene in 3 of 42 patients with B-NHL (7.1%). After screening by PCR-SSCP analysis, direct sequencing identified one missense mutation at codon 72 (nucleotide 233) and two frameshifts due to a 35-bp deletion arising at codon 49 (nucleotides 163 to 175) in patients with B-NHL (3 of 42, 7.1%). In the patient carrying the missense mutation, hemizygous deletion of the CDKN2 gene was also suspected. In this study, we detected alterations in CDKN2 in 6 of 42 patients (14.3%) with B-NHL and in none of 10 patients with B-CLL. Our results suggest that the CDKN2 alterations contribute in tumorigenesis in some patients with B-NHL.

scholarly journals Identification of a Novel de Novo Variant in the SYT2 Gene Causing a Rare Type of Distal Hereditary Motor Neuropathy

Genes ◽  
2020 ◽  
Vol 11 (11) ◽  
pp. 1238
Author(s):  
Olga Mironovich ◽  
Elena Dadali ◽  
Sergey Malmberg ◽  
Tatyana Markova ◽  
Oxana Ryzhkova ◽  
...  
Keyword(s):  
Missense Mutation ◽  
Clinical Presentation ◽  
De Novo ◽  
Clinical Manifestations ◽  
Motor Neuropathy ◽  
Rare Type ◽  
Hereditary Motor ◽  
Electrophysiological Testing ◽  
Hereditary Motor Neuropathy ◽  
De Novo Variant

Objective: To report the first de novo missense mutation in the SYT2 gene causing distal hereditary motor neuropathy. Methods: Genetic testing was carried out, including clinical exome sequencing for the proband and Sanger sequencing for the proband and his parents. We described the clinical and electrophysiological features found in the patient. Results: We reported a proband with a new de novo missense mutation, c.917C>T (p.Ser306Leu), in the C2B domain of SYT2. The clinical presentation was similar to that of phenotypes described in previous studies. A notable feature in our study was normal electrophysiological testing results of the patient. Conclusions: In this study we reinforced the association between SYT2 mutations and distal hereditary motor neuropathy. We also described the clinical presentation of the patient carrying this pathogenic variant and provided unusual results of electrophysiological testing. The results showed that a diagnosis of SYT2-associated neuropathy should be based on the similarity of clinical manifestations, rather than the results of electrophysiological testing.

Novel ABCD1 gene mutations in Iranian pedigrees with X-linked adrenoleukodystrophy

2019 ◽  
Vol 32 (11) ◽  
pp. 1207-1215
Author(s):  
Babak Emamalizadeh ◽  
Yousef Daneshmandpour ◽  
Abbas Tafakhori ◽  
Sakineh Ranji-Burachaloo ◽  
Sajad Shafiee ◽  
...  
Keyword(s):  
Protein Structure ◽  
Direct Sequencing ◽  
Gene Mutations ◽  
Protein Product ◽  
Structure And Function ◽  
Novel Mutations ◽  
Chain Reaction ◽  
Abcd1 Gene ◽  
Polymerase Chain ◽  
And Function

Abstract Background X-linked adrenoleukodystrophy (X-ALD), the most common peroxisomal disorder, is caused by mutations in the ABCD1 gene located on Xq28. X-ALD is characterized by a spectrum of different manifestations varying in patients and families. Methods Four pedigrees with X-ALD consisting of patients and healthy members were selected for investigation of ABCD1 gene mutations. The mutation analysis was performed by polymerase chain reaction (PCR) followed by direct sequencing of all exons. The identified mutations were investigated using bioinformatics tools to predict their effects on the protein product and also to compare the mutated sequence with close species. Results One previously known missense mutation (c.1978 C > T) and three novel mutations (c.1797dupT, c.879delC, c.1218 C > G) were identified in the ABCD1 gene, each in one family. Predicting the effects of the mutations on protein structure and function indicated the probable damaging effect for them with significant alterations in the protein structure. We found three novel mutations in the ABCD1 gene with damaging effects on its protein product and responsible for X-ALD.

scholarly journals Differential expression of KvLQT1 and its regulator IsK in mouse epithelia

2001 ◽  
Vol 280 (2) ◽  
pp. C359-C372 ◽  
Author(s):  
Sophie Demolombe ◽  
Diego Franco ◽  
Piet de Boer ◽  
Sabina Kuperschmidt ◽  
Dan Roden ◽  
...  
Keyword(s):  
Slow Component ◽  
Genetic Disorder ◽  
Expression Patterns ◽  
Resting Potential ◽  
Delayed Rectifier ◽  
Coding Region ◽  
Epithelial Tissues ◽  
In Situ Data ◽  
Adult Mice

KCNQ1 is the human gene responsible in most cases for the long QT syndrome, a genetic disorder characterized by anomalies in cardiac repolarization leading to arrhythmias and sudden death. KCNQ1 encodes a pore-forming K+channel subunit termed KvLQT1 which, in association with its regulatory β-subunit IsK (also called minK), produces the slow component of the delayed-rectifier cardiac K+ current. We used in situ hybridization to localize KvLQT1 and IsK mRNAs in various tissues from adult mice. We showed that KvLQT1 mRNA expression is widely distributed in epithelial tissues, in the absence (small intestine, lung, liver, thymus) or presence (kidney, stomach, exocrine pancreas) of its regulator IsK. In the kidney and the stomach, however, the expression patterns of KvLQT1 and IsK do not coincide. In many tissues, in situ data obtained with the IsK probe coincide with β-galactosidase expression in IsK-deficient mice in which the bacterial lacZgene has been substituted for the IsK coding region. Because expression of KvLQT1 in the presence or absence of its regulator generates a K+ current with different biophysical characteristics, the role of KvLQT1 in epithelial cells may vary depending on the expression of its regulator IsK. The high level of KvLQT1 expression in epithelial tissues is consistent with its potential role in K+secretion and recycling, in maintaining the resting potential, and in regulating Cl− secretion and/or Na+absorption.

scholarly journals MAMLD1 Gene Mutation in the Incidence of Hypospadias in the Chinese Population

2014 ◽  
Vol 33 (4) ◽  
pp. 341-346 ◽  
Author(s):  
Likai Zhuang ◽  
Ming Bai ◽  
Wei Zhou ◽  
Yongguo Yu ◽  
Jian Wang ◽  
...  
Keyword(s):  
Missense Mutation ◽  
Chinese Population ◽  
Direct Sequencing ◽  
Control Group ◽  
Normal Children ◽  
Mutation Site ◽  
Significant Difference ◽  
The Difference ◽  
New Research ◽  
Experimental Group

Summary Background: This study aimed to investigate the significance of MAMLD1 mutations in the incidence of hypospa-dias in a Chinese population. Methods: The experimental group consisted of 150 domestic children with hypospadias, aged 0.5 to six years and living in different provinces. A total of 120 normal children, aged two to six years, served as the control group. DNA was extracted for the direct sequencing of MAMLD1 genes. Results: Twelve cases (8.0%) of the missense mutation p.N589S were found in the experimental group, whereas four cases (3.0%) of the same mutation were found in the control group. No significant difference was observed in the mutation rate between the two groups (P>0.05). Four cases (2.7%) had a new missense mutation p.P567S in the experimental group, and three cases (2.5%) possessed the same mutation in the control group. No significant difference was observed between the two groups (P>0.05). Conclusions: In this study, the importance of repeated experiments in mutation-related studies was confirmed, which revealed the difference in predisposing genes among different populations. Although the mutation of the MAMLD1 gene had no apparent connection with the incidence of hypospadias in a Chinese population, a new mutation site of the MAMLD1 gene was discovered, which could provide new research topics for future studies.

scholarly journals Genetic Analysis of Aldosterone Synthase in Patients with Idiopathic Hyperaldosteronism1

1999 ◽  
Vol 84 (5) ◽  
pp. 1633-1637
Author(s):  
Yoshiyu Takeda ◽  
Kenji Furukawa ◽  
Satoru Inaba ◽  
Isamu Miyamori ◽  
Hiroshi Mabuchi
Keyword(s):  
Messenger Rna ◽  
Direct Sequencing ◽  
Renin Angiotensin System ◽  
Mononuclear Leukocytes ◽  
Coding Region ◽  
Angiotensin System ◽  
Aldosterone Synthase ◽  
Aldosterone Producing Adenoma ◽  
Pcr Method ◽  
Normal Controls

Idiopathic hyperaldosteronism (IHA) is characterized by hypertension with excessive production of aldosterone, potassium loss, and suppression of the renin-angiotensin system. We compared activity of aldosterone synthase and expression of CYP11B2 messenger RNA (mRNA) in mononuclear leukocytes (MNL) from patients with IHA to findings in leukocytes from patients with aldosterone-producing adenoma and normal controls. Aldosterone synthase activity was estimated from conversion of [14C]deoxycorticosterone to[ 14C]aldosterone. Levels of CYP11B2 mRNA were determined by competitive PCR. In the same subjects, we sought the chimeric CYP11B1/CYP11B2 that is candidate gene for glucocorticoid-remediable hyperaldosteronism. Southern blot analysis and a long PCR method were used to detect the chimeric gene. Direct sequencing of the CYP11B2 also was performed. No chimeric genes or mutations in the coding region of the CYP11B2 were found in genomic DNA from these patients. However, both aldosterone synthase activity and CYP11B2 mRNA expression were greater in mononuclear leukocytes of patients with IHA than those of patients with aldosterone-producing adenoma or controls. These results suggest that regulatory factors of the CYP11B2 gene, e.g. unidentified aldosterone-stimulating substances or abnormalities in the promoter region of the CYP11B2 gene in patients with IHA resulting in oversecretion, may cause overexpression of mRNA of CYP11B2.

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