scholarly journals A novel mutation in the calcium-sensing receptor in a French family with familial hypocalciuric hypercalcaemia

2011 ◽  
Vol 165 (2) ◽  
pp. 359-363 ◽  
Author(s):  
Abdallah Al-Salameh ◽  
Filomena Cetani ◽  
Elena Pardi ◽  
Carmen Vulpoi ◽  
Peggy Pierre ◽  
...  
Keyword(s):  
Inositol Phosphates ◽  
Novel Mutation ◽  
Dominant Negative ◽  
Calcium Handling ◽  
Dominant Negative Effect ◽  
Base Substitution ◽  
Calcium Sensing Receptor ◽  
Calcium Sensing ◽  
Extensive Evaluation ◽  
Negative Effect

ObjectiveThe calcium-sensing receptor (CASR) has an important role in calcium homoeostasis by controlling PTH secretion and renal calcium handling. Inactivating mutations in the CASR gene (HGNC ID: 1514) cause familial hypocalciuric hypercalcaemia (FHH). We present a case of FHH patient to describe a novel mutation in the CASR.Subjects and methodsA 34-year-old patient was referred because of recurrent hypercalcaemia after resection of two hyperplastic parathyroids. Extensive evaluation found elevated PTH and low calcium/creatinine clearance ratio. One of her three children had high serum calcium concentrations. Genetic studies were performed by PCR amplification of CASR coding exons and direct sequencing of PCR products. Transient transfection of the wild-type (WT) CASR and the mutant CASR into COS-7 was performed to assess functional impact of the mutation and the capacity of either protein to mediate increases in cellular levels of inositol phosphates (IPs).ResultsCASR sequencing found a previously undescribed heterozygous base substitution, determining a change of threonine to isoleucine at codon 550 (p.T550I) in the sixth exon. In contrast to those transfected with WT CASR, which showed a five- to eightfold increase in total IPs at high levels of calcium, COS-7 cells transfected with the (p.T550I) mutant showed no increase confirming to the inactivating nature of the mutation. COS-7 cells co-transfected with the WT and the (p.T550I) mutant showed an intermediate response suggesting a possible dominant negative effect.ConclusionThis case report presents a not-yet-described mutation in the cysteine-rich region of the CASR extracellular domain, a mutation with a possible dominant negative effect.

A Novel Mutation in EFNB1, Probably with a Dominant Negative Effect, Underlying Craniofrontonasal Syndrome

2006 ◽  
Vol 43 (2) ◽  
pp. 152-154 ◽  
Author(s):  
Vorasuk Shotelersuk ◽  
Pichit Siriwan ◽  
Surasawadee Ausavarat
Keyword(s):  
Amino Acids ◽  
Novel Mutation ◽  
Clinical Manifestations ◽  
Dominant Negative ◽  
Soluble Form ◽  
Dominant Negative Effect ◽  
Truncated Protein ◽  
Frontonasal Dysplasia ◽  
Thai Woman ◽  
Negative Effect

Craniofrontonasal syndrome (CFNS) is an X-linked disorder whose main clinical manifestations include coronal craniosynostosis and frontonasal dysplasia. Very recently, CFNS was shown to be caused by mutations in EFNB1 encoding ephrin-B1, and 20 mutations have been described. We report a Thai woman with CFNS, in whom a novel mutation was discovered: c.685_686insG, in exon 5 of EFNB1. It is the first insertion and the most 3′ point mutation in EFNB1 reported to date. The mutation is expected to result in a truncated ephrin-B1 of 230 amino acids, composed of a nearly complete extracellular part of ephrin-B1 with no transmembrane and cytoplasmic domains. This truncated protein might become a soluble form of the ligand, which previously was shown to be able to bind to receptors, but fail to cluster and to activate them—in other words, acting as a dominant negative protein. Nonetheless, further studies to detect the protein are needed to substantiate the hypothesis.

scholarly journals A Novel Mutation in KCNQ1 Associated with a Potent Dominant Negative Effect as the Basis for the LQT1 Form of the Long QT Syndrome

2007 ◽  
Vol 18 (9) ◽  
pp. 972-977 ◽  
Author(s):  
YOSHIYASU AIZAWA ◽  
KAZUO UEDA ◽  
FABIANA SCORNIK ◽  
JONATHAN M. CORDEIRO ◽  
YUESHENG WU ◽  
...  
Keyword(s):  
Long Qt Syndrome ◽  
Novel Mutation ◽  
Dominant Negative ◽  
Dominant Negative Effect ◽  
Long Qt ◽  
Negative Effect ◽  
Qt Syndrome

scholarly journals Complex inheritance pattern of dyskeratosis congenita in two families with 2 different mutations in the telomerase reverse transcriptase gene

Blood ◽  
2008 ◽  
Vol 111 (3) ◽  
pp. 1128-1130 ◽  
Author(s):  
Hong-Yan Du ◽  
Elena Pumbo ◽  
Peter Manley ◽  
Joshua J. Field ◽  
Susan J. Bayliss ◽  
...  
Keyword(s):  
Reverse Transcriptase ◽  
Novel Mutation ◽  
Dyskeratosis Congenita ◽  
Dominant Negative ◽  
Dominant Negative Effect ◽  
Telomere Shortening ◽  
Intragenic Complementation ◽  
Negative Effect ◽  
Complex Inheritance ◽  
Compound Heterozygotes

Abstract Heterozygous mutations in the telomerase components TERT, the reverse transcriptase, and TERC, the RNA template, cause autosomal dominant dyskeratosis congenita due to telomere shortening. Anticipation, whereby the disease severity increases in succeeding generations due to inheritance of shorter telomeres, is a feature of this condition. Here we describe 2 families in which 2 TERT mutations are segregating. Both families contain compound heterozygotes. In one case the proband is homozygous for a novel mutation causing a P704S substitution, while his father's second allele encodes an H412Y mutation. The proband in the second family has mutant alleles Y846C and H876Q. Transfection studies show codominant expression of the mutated alleles with no evidence of a dominant negative effect or of intragenic complementation. Thus in these families the expression of both TERT alleles and the inherited telomere length contribute to the clinical phenotype.

scholarly journals Novel mutation in the ALPL gene with a dominant negative effect in a Japanese family

2021 ◽  
Author(s):  
Masaru Kato ◽  
Toshimi Michigami ◽  
Kanako Tachikawa ◽  
Momoko Kato ◽  
Ichiro Yabe ◽  
...  
Keyword(s):  
Novel Mutation ◽  
Dominant Negative ◽  
Dominant Negative Effect ◽  
Japanese Family ◽  
Negative Effect

scholarly journals A Dominant Negative Effect of eth-1r, a Mutant Allele of the Neurospora crassa S-Adenosylmethionine Synthetase-Encoding Gene Conferring Resistance to the Methionine Toxic Analogue Ethionine

Genetics ◽  
1996 ◽  
Vol 144 (4) ◽  
pp. 1455-1462
Author(s):  
José L Barra ◽  
Mario R Mautino ◽  
Alberto L Rosa
Keyword(s):  
Neurospora Crassa ◽  
Dominant Negative ◽  
Dominant Negative Effect ◽  
Resistant Phenotype ◽  
Negative Effect ◽  
Encoding Gene ◽  
Adenosylmethionine Synthetase ◽  
Adomet Synthetase ◽  
Identical Gene

eth-1r a thermosensitive allele of the Neurospora crassa S-adenosylmethionine (AdoMet) synthetase gene that confers ethionine resistance, has been cloned and sequenced. Replacement of an aspartic amino acid residue (D48 → N48), perfectly conserved in prokaryotic, fungal and higher eukaryotic AdoMet synthetases, was found responsible for both thermosensitivity and ethionine resistance conferred by eth-1r. Gene fusion constructs, designed to overexpress eth-1r in vivo, render transformant cells resistant to ethionine. Dominance of ethionine resistance was further demonstrated in eth-1  +/eth-1r partial diploids carrying identical gene doses of both alleles. Heterozygous eth-1  +/eth-1r cells have, at the same time, both the thermotolerance conferred by eth-1  + and the ethionine-resistant phenotype conferred by eth-1r. AdoMet levels and AdoMet synthetase activities were dramatically decreased in heterozygous eth-1  +/eth-1r cells. We propose that this negative effect exerted by eth-1r results from the in vivo formation of heteromeric eth-1  +/eth-1r AdoMet synthetase molecules.

scholarly journals Restoration of Silencing in Saccharomyces cerevisiae by Tethering of a Novel Sir2-Interacting Protein, Esc8

Genetics ◽  
2002 ◽  
Vol 162 (2) ◽  
pp. 633-645 ◽  
Author(s):  
Guido Cuperus ◽  
David Shore
Keyword(s):  
Protein A ◽  
Dominant Negative ◽  
Class I ◽  
Dominant Negative Effect ◽  
Rna Pol Ii ◽  
Interacting Protein ◽  
Nucleosome Remodeling ◽  
Negative Effect ◽  
Close Homolog

Abstract We previously described two classes of SIR2 mutations specifically defective in either telomeric/HM silencing (class I) or rDNA silencing (class II) in S. cerevisiae. Here we report the identification of genes whose protein products, when either overexpressed or directly tethered to the locus in question, can establish silencing in SIR2 class I mutants. Elevated dosage of SCS2, previously implicated as a regulator of both inositol biosynthesis and telomeric silencing, suppressed the dominant-negative effect of a SIR2-143 mutation. In a genetic screen for proteins that restore silencing when tethered to a telomere, we isolated ESC2 and an uncharacterized gene, (YOL017w), which we call ESC8. Both Esc2p and Esc8p interact with Sir2p in two-hybrid assays, and the Esc8p-Sir2 interaction is detected in vitro. Interestingly, Esc8p has a single close homolog in yeast, the ISW1-complex factor Ioc3p, and has also been copurified with Isw1p, raising the possibility that Esc8p is a component of an Isw1p-containing nucleosome remodeling complex. Whereas esc2 and esc8 deletion mutants alone have only marginal silencing defects, cells lacking Isw1p show a strong silencing defect at HMR but not at telomeres. Finally, we show that Esc8p interacts with the Gal11 protein, a component of the RNA pol II mediator complex.

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