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Acute liver failure meets SOPH syndrome: A case report on an intermediate phenotype.

https://arctichealth.org/en/permalink/ahliterature283558
Source
Pediatrics. 2017 Jan;139(1)
Publication Type
Article
Date
Jan-2017
Author
Fanny Kortüm
Iris Marquardt
Malik Alawi
Georg Christoph Korenke
Stephanie Spranger
Peter Meinecke
Kerstin Kutsche
Source
Pediatrics. 2017 Jan;139(1)
Date
Jan-2017
Language
English
Publication Type
Article
Keywords
Alleles
Child, Preschool
DNA Mutational Analysis
Developmental Disabilities - diagnosis - genetics
Dwarfism - diagnosis - genetics
Exome - genetics
Female
Heterozygote Detection
Humans
Liver Failure, Acute - diagnosis - genetics
Mutation, Missense - genetics
Neoplasm Proteins - deficiency - genetics
Optic Atrophy - diagnosis - genetics
Pelger-Huet Anomaly - diagnosis - genetics
Phenotype
Syndrome
Abstract
Acute liver failure (ALF) is a life-threatening condition in the absence of preexisting liver disease in children. The main clinical presentation comprises hepatic dysfunction, elevated liver biochemical values, and coagulopathy. The etiology of ALF remains unclear in most affected children; however, the recent identification of mutations in the neuroblastoma amplified sequence (NBAS) gene in autosomal recessively inherited ALF has shed light on the cause of a subgroup of fever-triggered pediatric ALF episodes. Previously, biallelic mutations in NBAS have been reported to be associated with a syndrome comprising short stature, optic atrophy, and Pelger-Huët anomaly (SOPH) specifically occurring in the Yakut population. No hepatic phenotype has been observed in individuals with this disorder who all carry the homozygous NBAS founder mutation c.5741G>A [p.(Arg1914His)]. We present the case of a 4-year-old girl with the cardinal features of SOPH syndrome: characteristic facial dysmorphism, postnatal growth retardation, delay of bone age, slender long bones, optic atrophy, and Pelger-Huët anomaly. During the first 2 years of her life, a series of infections with episodes of fever were accompanied by elevated liver enzyme levels, but hyperammonemia, hypoglycemia, coagulopathy, or encephalopathy suggestive of acute and severe liver disease were never observed. Whole exome sequencing in the patient revealed compound heterozygosity of the 2 NBAS variants, p.(Arg1914His) and p.(Glu943*). This case highlights the variability of clinical presentation associated with NBAS deficiency. Absence of severe liver problems in this case and SOPH-affected Yakut subjects suggests that individuals carrying the NBAS missense mutation p.(Arg1914His) are less susceptible to developing ALF.
PubMed ID
28031453 View in PubMed
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Adrenomyeloneuropathy: report of a new mutation in a French Canadian female.

https://arctichealth.org/en/permalink/ahliterature173849
Source
Can J Neurol Sci. 2005 May;32(2):261-3
Publication Type
Article
Date
May-2005
Author
Annie Dionne
Denis Brunet
Alexander McCampbell
Nicolas Dupré
Author Affiliation
Départment des Sciences Neurologiques, CHAUQ-Hôpital Enfant-Jésus, McGill University, QC, Canada.
Source
Can J Neurol Sci. 2005 May;32(2):261-3
Date
May-2005
Language
English
Publication Type
Article
Keywords
ATP-Binding Cassette Transporters - genetics
Adrenoleukodystrophy - genetics - metabolism - physiopathology
Amino Acid Sequence - genetics
Amino Acid Substitution - genetics
Chromosomes, Human, X - genetics
DNA Mutational Analysis
Diagnosis, Differential
Exons - genetics
Family Health
Female
Genetic Testing
Humans
Middle Aged
Mutation, Missense - genetics
Pedigree
Phenotype
Quebec - ethnology
Sex Factors
Abstract
X-linked adrenoleukodystrophy is a peroxisomial disorder caused by mutations in the ABCD1 gene. Adrenomyeloneuropathy is the second most frequent phenotype (25-46%) of this disease and classically presents in adulthood with spastic paraparesis. Female heterozygotes can be symptomatic, but they are frequently misdiagnosed as having multiple sclerosis.
We report a novel missense mutation in the ABCD1 gene in a 47-year-old French-Canadian female with spastic paraparesis and no confirmed family history of X-linked adrenoleukodystrophy. The mutation is located on exon 1 and causes the amino acid substitution of a valine for an alanine in a region of the protein highly conserved between mouse and man.
Adrenomyeloneuropathy must be considered in the differential diagnosis of spastic paraparesis in men or women. This is an initial report of an ABCD1 gene mutation in the French-Canadian population, which should lead to the recognition of other cases in the future.
PubMed ID
16018167 View in PubMed
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Alterations of E-cadherin and beta-catenin in gastric cancer.

https://arctichealth.org/en/permalink/ahliterature19398
Source
BMC Cancer. 2001;1:16
Publication Type
Article
Date
2001
Author
C. Huiping
S. Kristjansdottir
J G Jonasson
J. Magnusson
V. Egilsson
S. Ingvarsson
Author Affiliation
Department of Pathology, National University Hospital, 101 Reykjavík, Iceland. chen@rsp.is
Source
BMC Cancer. 2001;1:16
Date
2001
Language
English
Publication Type
Article
Keywords
Age of Onset
Aged
Breast Neoplasms - genetics - pathology
Cadherins - genetics - physiology
Cell Adhesion - genetics - physiology
Chromosomes, Human, Pair 16 - genetics
Cytoskeletal Proteins - genetics - physiology
DNA Mutational Analysis - methods
DNA, Neoplasm - genetics
Female
Gene Expression Regulation, Neoplastic - genetics - physiology
Germ-Line Mutation - genetics - physiology
Humans
Loss of Heterozygosity - genetics
Male
Mutation, Missense - genetics - physiology
Prostatic Neoplasms - genetics - pathology
Research Support, Non-U.S. Gov't
Skin Neoplasms - genetics - pathology
Stomach Neoplasms - genetics - pathology
Trans-Activators - genetics - physiology
beta Catenin
Abstract
BACKGROUND: The E-cadherin-catenin complex plays a crucial role in epithelial cell-cell adhesion and in the maintenance of tissue architecture. Perturbation in the expression or function of this complex results in loss of intercellular adhesion, with possible consequent cell transformation and tumour progression. METHODS: We studied the alterations of E-cadherin and beta-catenin in a set of 50 primary gastric tumours by using loss of heterozygosity (LOH) analysis, gene mutation screening, detection of aberrant transcripts and immunohistochemistry (IHC). RESULTS: A high frequency (75%) of LOH was detected at 16q22.1 containing E-cadherin locus. Three cases (6%) showed the identical missense mutation, A592T. This mutation is not likely to contribute strongly to the carcinogenesis of gastric cancer, because a low frequency (1.6%) of this mutation was also found in 187 normal individuals. We also detected a low frequency (0.36%, 0%) of this mutation in 280 breast tumours and 444 other tumours, including colon and rectum, lung, endometrium, ovary, testis, kidney, thyroid carcinomas and sarcomas, respectively. We also analyzed the aberrant E-cadherin mRNAs in the gastric tumours and found that 7 tumours (18%) had aberrant mRNAs in addition to the normal mRNA. These aberrant mRNAs may produce abnormal E-cadherin molecules, resulting in weak cell-cell adhesion and invasive behaviour of carcinoma cells. Reduced expression of E-cadherin and beta-catenin was identified at the frequency of 42% and 28%, respectively. Specially, 11 tumours (22%) exhibited positive cytoplasmic staining for beta-catenin IHC. An association was found between reduced expression of E-cadherin and beta-catenin. Moreover, an association was detected between reduced expression of E-cadherin and diffuse histotype. CONCLUSION: Our results support the hypothesis that alterations of E-cadherin and beta-catenin play a role in the initiation and progression of gastric cancer.
PubMed ID
11747475 View in PubMed
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APC I1307K and E1317Q variants are rare or do not occur in Swedish colorectal cancer patients.

https://arctichealth.org/en/permalink/ahliterature19920
Source
Eur J Cancer. 2001 Mar;37(4):499-502
Publication Type
Article
Date
Mar-2001
Author
S. Evertsson
A. Lindblom
X F Sun
Author Affiliation
Department of Oncology, Institute of Biomedicine and Surgery, Linköping University, S-581 85, Linköping, Sweden.
Source
Eur J Cancer. 2001 Mar;37(4):499-502
Date
Mar-2001
Language
English
Publication Type
Article
Keywords
Aged
Aged, 80 and over
Arabidopsis Proteins
Calcium-Binding Proteins - genetics
Colorectal Neoplasms - epidemiology - genetics
Female
Humans
Male
Middle Aged
Mutation, Missense - genetics
Pedigree
Polymerase Chain Reaction - methods
Research Support, Non-U.S. Gov't
Sweden - epidemiology - ethnology
Abstract
Recently, a germ line mutation of the APC gene, I1307K, was discovered in a subset of Ashkenazi jews. The mutation involves an amino acid exchange and creates a tract consisting of eight contiguous adenosine residues believed to cause hypermutability in this region. Another germ line missense variant, E1317Q, not restricted to a certain ethnic population, could functionally alter the protein. These APC variants have been linked with increased colorectal cancer risk in several studies. However, they have not yet been investigated in Swedish colorectal cancer patients. Thus, our aim was to investigate the prevalence of I1307K and E1317Q in Swedish colorectal cancer patients in order to determine if these genetic variants are important predisposing factors to colorectal cancer in this population. To this end, sequence analysis was carried out of the APC gene in order to identify any I1307K and E1317Q variants in 106 unselected cases and 88 hereditary/familial colorectal cancer cases including 22 cases of hereditary non-polyposis colorectal cancer (HNPCC) fulfilling the Amsterdam criteria. Out of a total of 194 cases examined, we did not find any variants. It seems that these alterations are rare or absent in the Swedish population.
PubMed ID
11267860 View in PubMed
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BARD1 variants Cys557Ser and Val507Met in breast cancer predisposition.

https://arctichealth.org/en/permalink/ahliterature171664
Source
Eur J Hum Genet. 2006 Feb;14(2):167-72
Publication Type
Article
Date
Feb-2006
Author
Pia Vahteristo
Kirsi Syrjäkoski
Tuomas Heikkinen
Hannaleena Eerola
Kristiina Aittomäki
Karl von Smitten
Kaija Holli
Carl Blomqvist
Olli-Pekka Kallioniemi
Heli Nevanlinna
Author Affiliation
Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Helsinki, Finland. pia.vahteristo@helsinki.fi
Source
Eur J Hum Genet. 2006 Feb;14(2):167-72
Date
Feb-2006
Language
English
Publication Type
Article
Keywords
Breast Neoplasms - genetics
DNA Mutational Analysis
Female
Finland
Gene Frequency
Genetic Predisposition to Disease
Genotype
Humans
Mutation, Missense - genetics
Tumor Suppressor Proteins - genetics
Ubiquitin-Protein Ligases - genetics
Abstract
BARD1 (BRCA1-associated RING-domain 1) is a tumor suppressor whose protein product interacts with BRCA1, and in which rare somatic and germline mutations have been reported in breast, uterine, and endometrial cancers. We aimed to evaluate whether there are BARD1 genetic variants that contribute to breast cancer risk by screening the gene for germline alterations in 45 Finnish familial breast cancer patients and in seven patients with both breast and ovarian cancer. Two of the missense alterations identified (Cys557Ser and Val507Met) were recently suggested to associate with an increased breast cancer risk. We also analyzed these variants in large and independent series of familial and unselected breast cancer patients and healthy controls. No clearly deleterious mutations were detected in the initial mutation screening. No association of the Cys557Ser and breast cancer risk was observed as the variant was found altogether in 1.4% (16/1181) of familial and 2.2% (34/1565) of unselected breast cancer patients, and in 2.5% (27/1083) of healthy controls. The frequency of the Val-allele of the Val507Met variant was modestly higher among breast cancer patients than among healthy controls, although the difference did not reach statistical significance. No statistically significant association of the Cys557Ser or Val507Met variants with any clinicopathologic parameters was observed. These results suggest that the contribution of the BARD1 germline variants to breast cancer predisposition is very limited, and that neither Cys557Ser nor Val507Met have an effect on familial breast cancer susceptibility.
PubMed ID
16333312 View in PubMed
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C1q deficiency in an Inuit family: identification of a new class of C1q disease-causing mutations.

https://arctichealth.org/en/permalink/ahliterature163475
Source
Clin Immunol. 2007 Jul;124(1):33-40
Publication Type
Article
Date
Jul-2007
Author
Hanne Vibeke Marquart
Lone Schejbel
Anders Sjoholm
Ulla Martensson
Susan Nielsen
Anders Koch
Arne Svejgaard
Peter Garred
Author Affiliation
Dept. of Clinical Immunology sect. 7631, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, Denmark. hanne.marquart@rh.hosp.dk
Source
Clin Immunol. 2007 Jul;124(1):33-40
Date
Jul-2007
Language
English
Publication Type
Article
Keywords
Adolescent
Arginine - genetics
Child
Child, Preschool
Complement C1q - deficiency - genetics
Complement Hemolytic Activity Assay
Consanguinity
Female
Glycine - genetics
Greenland
Homozygote
Humans
Inuits - genetics
Lupus Erythematosus, Systemic - genetics - immunology - pathology
Mutation, Missense - genetics
Pedigree
Point Mutation - genetics
Sequence Homology, Amino Acid
Siblings
Abstract
C1q deficiency is a rare condition associated with a systemic lupus erythematosus (SLE)-like syndrome and recurrent infections. Here we present the molecular basis behind C1q deficiency in three sisters of Inuit origin. Initial examination for complement deficiency showed no function of the classical complement activation pathway in the patients; the lectin and alternative pathways were intact. No C1q or low molecular weight C1q was detected in sera and no anti-C1q autoantibodies were found. Sequencing of the C1q genes revealed a novel missense mutation (Gly-Arg) in codon 217 of the B chain. All sisters were homozygous for the mutation: both parents were heterozygous. None of 100 healthy controls carried the mutation. Our findings define a third class of molecular mechanisms behind C1q deficiency, where missense mutations cause a lack of detectable C1q-antigen in serum.
PubMed ID
17513176 View in PubMed
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Cardiac sodium channel dysfunction in sudden infant death syndrome.

https://arctichealth.org/en/permalink/ahliterature79209
Source
Circulation. 2007 Jan 23;115(3):368-76
Publication Type
Article
Date
Jan-23-2007
Author
Wang Dao W
Desai Reshma R
Crotti Lia
Arnestad Marianne
Insolia Roberto
Pedrazzini Matteo
Ferrandi Chiara
Vege Ashild
Rognum Torleiv
Schwartz Peter J
George Alfred L
Author Affiliation
Departments of Pharmacology, Vanderbilt University, Nashville, Tenn, USA.
Source
Circulation. 2007 Jan 23;115(3):368-76
Date
Jan-23-2007
Language
English
Publication Type
Article
Keywords
Alleles
Arrhythmia - complications - genetics - physiopathology
Cohort Studies
DNA, Complementary - genetics
Electrocardiography
Electrophysiology
Gene Expression Regulation
Genetic Predisposition to Disease
Genetic Screening - methods
Humans
Infant
Long QT Syndrome - complications - genetics - physiopathology
Mathematics
Muscle Proteins - genetics - physiology
Mutation, Missense - genetics
Norway
Phenotype
Risk factors
Sodium Channels - genetics - physiology
Sudden Infant Death - etiology - genetics
Variation (Genetics) - genetics
Abstract
BACKGROUND: Mutations in genes responsible for the congenital long-QT syndrome, especially SCN5A, have been identified in some cases of sudden infant death syndrome. In a large-scale collaborative genetic screen, several SCN5A variants were identified in a Norwegian sudden infant death syndrome cohort (n=201). We present functional characterization of 7 missense variants (S216L, R680H, T1304M, F1486L, V1951L, F2004L, and P2006A) and 1 in-frame deletion allele (delAL586-587) identified by these efforts. METHODS AND RESULTS: Whole-cell sodium currents were measured in tsA201 cells transiently transfected with recombinant wild-type or mutant SCN5A cDNA (hH1) coexpressed with the human beta1 subunit. All variants exhibited defects in the kinetics and voltage dependence of inactivation. Five variants (S216L, T1304M, F1486L, F2004L, and P2006A) exhibited significantly increased persistent sodium currents (range, 0.5% to 1.7% of peak current) typical of SCN5A mutations associated with long-QT syndrome. These same 5 variants also displayed significant depolarizing shifts in voltage dependence of inactivation (range, 5 to 14 mV) and faster recovery from inactivation, but F1486L uniquely exhibits a depolarizing shift in the conductance-voltage relationship. Three alleles (delAL586-587, R680H, and V1951L) exhibited increased persistent current only under conditions of internal acidosis (R680H) or when expressed in the context of a common splice variant (delQ1077), indicating that they have a latent dysfunctional phenotype. CONCLUSIONS: Our present results greatly expand the spectrum of functionally characterized SCN5A variants associated with sudden infant death syndrome and provide further biophysical correlates of arrhythmia susceptibility in this syndrome.
PubMed ID
17210841 View in PubMed
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Clinical, histopathologic, and genetic investigation in two large families with dentinogenesis imperfecta type II.

https://arctichealth.org/en/permalink/ahliterature181675
Source
Hum Genet. 2004 Apr;114(5):491-8
Publication Type
Article
Date
Apr-2004
Author
B. Malmgren
S. Lindskog
A. Elgadi
S. Norgren
Author Affiliation
Department of Pediatrics, Pediatric Endocrine Research Unit, B62, Huddinge University Hospital, Karolinska Institutet, SE-141 86 Stockholm, Sweden. barbro.malmgren@telia.com
Source
Hum Genet. 2004 Apr;114(5):491-8
Date
Apr-2004
Language
English
Publication Type
Article
Keywords
Base Sequence
Case-Control Studies
DNA Primers
Dentin - pathology
Dentinogenesis Imperfecta - genetics - pathology
Electrophoresis, Polyacrylamide Gel
Extracellular Matrix Proteins
Haplotypes - genetics
Humans
Mutation, Missense - genetics
Pedigree
Phosphoproteins
Protein Precursors - genetics
Sequence Analysis, DNA
Sialoglycoproteins
Sweden
Tooth - pathology - radiography
Abstract
Dentinogenesis imperfecta (DI) type II, an inherited disorder affecting dentin, has been linked to mutations in the dentin sialophosphoprotein ( DSPP) gene on chromosome 4q21. The gene product is cleaved into two dentin-specific matrix proteins, dentin sialoprotein (DSP) and dentin phosphoprotein. The aim of this investigation was to study genotypes and phenotypes in two affected families with special reference to clinical, radiographic, and histopathologic manifestations. Seven affected members of Family A and five of Family B were documented clinically and radiographically; 14 and 10 teeth, respectively, were available for histopathologic investigation and prepared for ground sections, which were assessed semiquantitatively for dysplastic manifestations in the dentin according to the scoring system, dysplastic dentin score (DDS). Venous blood samples were collected from six affected and ten unaffected members of Family A, and from eight affected and six unaffected members of Family B. Genomic DNA was extracted and used for sequence analyses. The two families presented with different missense mutations. An Arg68Trp missense mutation in the DSP part of the gene was revealed in all six analyzed affected individuals in Family A. This mutation was not present in any of the ten healthy members. In Family B, an Ala15Val missense mutation involving the last residue of the signal peptide was found in all eight affected but in none of the six healthy members. The clinical and radiographic disturbances and DDS were more severe in Family B. The data indicate the presence of a genotype-phenotype correlation in DI type II.
PubMed ID
14758537 View in PubMed
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CLPB variants associated with autosomal-recessive mitochondrial disorder with cataract, neutropenia, epilepsy, and methylglutaconic aciduria.

https://arctichealth.org/en/permalink/ahliterature261522
Source
Am J Hum Genet. 2015 Feb 5;96(2):258-65
Publication Type
Article
Date
Feb-5-2015
Author
Carol Saunders
Laurie Smith
Flemming Wibrand
Kirstine Ravn
Peter Bross
Isabelle Thiffault
Mette Christensen
Andrea Atherton
Emily Farrow
Neil Miller
Stephen F Kingsmore
Elsebet Ostergaard
Source
Am J Hum Genet. 2015 Feb 5;96(2):258-65
Date
Feb-5-2015
Language
English
Publication Type
Article
Keywords
Abnormalities, Multiple - genetics - pathology
Atrophy - genetics - pathology
Base Sequence
Brain - pathology
Cataract - genetics - pathology
Child, Preschool
Codon, Nonsense - genetics
Endopeptidase Clp - genetics - metabolism
Epilepsy - genetics - pathology
Exome - genetics
Fatal Outcome
Female
Fibroblasts - metabolism
Genes, Recessive - genetics
Greenland
Humans
Infant
Infant, Newborn
Liver - metabolism
Male
Metabolism, Inborn Errors - genetics - pathology
Mitochondrial Diseases - genetics - pathology
Molecular Sequence Data
Movement Disorders - genetics - pathology
Mutation, Missense - genetics
Neutropenia - genetics - pathology
Sequence Analysis, DNA
Abstract
3-methylglutaconic aciduria (3-MGA-uria) is a nonspecific finding associated with mitochondrial dysfunction, including defects of oxidative phosphorylation. 3-MGA-uria is classified into five groups, of which one, type IV, is genetically heterogeneous. Here we report five children with a form of type IV 3-MGA-uria characterized by cataracts, severe psychomotor regression during febrile episodes, epilepsy, neutropenia with frequent infections, and death in early childhood. Four of the individuals were of Greenlandic descent, and one was North American, of Northern European and Asian descent. Through a combination of homozygosity mapping in the Greenlandic individuals and exome sequencing in the North American, we identified biallelic variants in the caseinolytic peptidase B homolog (CLPB). The causative variants included one missense variant, c.803C>T (p.Thr268Met), and two nonsense variants, c.961A>T (p.Lys321*) and c.1249C>T (p.Arg417*). The level of CLPB protein was markedly decreased in fibroblasts and liver of affected individuals. CLPB is proposed to function as a mitochondrial chaperone involved in disaggregation of misfolded proteins, resulting from stress such as heat denaturation.
Notes
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PubMed ID
25597511 View in PubMed
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A common genetic variant of luteinizing hormone; relation to normal and aberrant pituitary-gonadal function.

https://arctichealth.org/en/permalink/ahliterature195532
Source
Eur J Pharmacol. 2001 Feb 23;414(1):1-7
Publication Type
Article
Date
Feb-23-2001
Author
T. Lamminen
I. Huhtaniemi
Author Affiliation
Department of Physiology, University of Turku, Kiinamyllynkatu 10, 20520, Turku, Finland.
Source
Eur J Pharmacol. 2001 Feb 23;414(1):1-7
Date
Feb-23-2001
Language
English
Publication Type
Article
Keywords
Animals
Exons - genetics
Female
Gene Frequency - genetics
Glycoprotein Hormones, alpha Subunit - genetics
Gonads - physiology
Humans
Luteinizing Hormone - genetics
Male
Mutation, Missense - genetics
Obesity - genetics
Pituitary Gland - physiology
Point Mutation - genetics
Polycystic Ovary Syndrome - genetics
Polymorphism, Genetic - genetics
Receptors, LH - physiology
Abstract
Mutations of the luteinizing hormone (LH) subunit genes are extremely rare. Only one polymorphic LHbeta gene variant makes an exception. In 1992, an immunologically anomalous form of LH was found in a healthy woman, and it was subsequently found to be caused by two point mutations leading to two amino acid substitutions in the LHbeta subunit. Of the two point mutations, Trp(8)Arg and Ile(15)Thr, the first one is mainly responsible for the altered immunoreactivity and the latter one introduces an extra glycosylation site into Asn(13) of the mutated LHbeta peptide. The frequency of this variant LHbeta allele differs widely between ethnic groups, being most common in aboriginal Australians (carrier frequency >50%; allelic frequency 28.3%) and totally lacking from Kotas of Southern India. Functional differences have been detected when wild-type LH and variant LH have been compared. Variant LH possesses increased in vitro bioactivity, whereas its half-life in circulation is shorter in comparison to wild-type LH. Also the regulation of the variant LHbeta gene differs due to additional changes in its promoter sequence. Correlations of occurrence of variant LH with various clinical conditions involving LH function suggest that it represents a biologically less active form of LH and may be related to borderline suppression of gonadal function, including subfertility. In this article, we will review the current information about the differences observed in structure and functions between the wild-type and variant LH, as well as their possible pathophysiological correlations.
PubMed ID
11230989 View in PubMed
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76 records – page 1 of 8.