scholarly journals A Third MLPH Variant Causing Coat Color Dilution in Dogs

Genes ◽  
2020 ◽  
Vol 11 (6) ◽  
pp. 639
Author(s):  
Samantha L. Van Buren ◽  
Katie M. Minor ◽  
Robert A. Grahn ◽  
James R. Mickelson ◽  
Jennifer C. Grahn ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Coat Color ◽  
Stop Codon ◽  
Premature Stop Codon ◽  
Low Frequency ◽  
Allelic Heterogeneity ◽  
Recessive Inheritance ◽  
Compound Heterozygotes

Altered melanosome transport in melanocytes, resulting from variants in the melanophilin (MLPH) gene, are associated with inherited forms of coat color dilution in many species. In dogs, the MLPH gene corresponds to the D locus and two variants, c.−22G > A (d1) and c.705G > C (d2), leading to the dilution of coat color, as described. Here, we describe the independent investigations of dogs whose coat color dilution could not be explained by known variants, and who report a third MLPH variant, (c.667_668insC) (d3), which leads to a frameshift and premature stop codon (p.His223Profs*41). The d3 allele is found at low frequency in multiple dog breeds, as well as in wolves, wolf-dog hybrids, and indigenous dogs. Canids in which the d3 allele contributed to the grey (dilute) phenotype were d1/d3 compound heterozygotes or d3 homozygotes, and all non-dilute related dogs had one or two D alleles, consistent with a recessive inheritance. Similar to other loci responsible for coat colors in dogs, this, alongside likely additional allelic heterogeneity at the D locus, or other loci, must be considered when performing and interpreting genetic testing.

scholarly journals A Novel Frameshift Mutation of SCNN1G Causing Liddle Syndrome with Normokalemia

2019 ◽  
Vol 32 (8) ◽  
pp. 752-758
Author(s):  
Peng Fan ◽  
Yu-Mo Zhao ◽  
Di Zhang ◽  
Ying Liao ◽  
Kun-Qi Yang ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Frameshift Mutation ◽  
Stop Codon ◽  
Single Gene ◽  
Family Members ◽  
Premature Stop Codon ◽  
Chinese Family ◽  
Autosomal Dominant Disorder ◽  
Liddle Syndrome ◽  
Genetic Sequencing

Abstract BACKGROUND Liddle syndrome (LS) is an autosomal dominant disorder caused by single-gene mutations of the epithelial sodium channel (ENaC). It is characterized by early-onset hypertension, spontaneous hypokalemia and low plasma renin and aldosterone concentrations. In this study, we reported an LS pedigree with normokalemia resulting from a novel SCNN1G frameshift mutation. METHODS Peripheral blood samples were collected from the proband and eight family members for DNA extraction. Next-generation sequencing and Sanger sequencing were performed to identify the SCNN1G mutation. Clinical examinations were used to comprehensively evaluate the phenotypes of two patients. RESULTS Genetic analysis identified a novel SCNN1G frameshift mutation, p.Arg586Valfs*598, in the proband with LS. This heterozygous frameshift mutation generated a premature stop codon and deleted the vital PY motif of ENaC. The same mutation was present in his elder brother with LS, and his mother without any LS symptoms. Biochemical examination showed normokalemia in the three mutation carriers. The mutation identified was not found in any other family members, 100 hypertensives, or 100 healthy controls. CONCLUSIONS Our study identified a novel SCNN1G frameshift mutation in a Chinese family with LS, expanding the genetic spectrum of SCNN1G. Genetic testing helped us identify LS with a pathogenic mutation when the genotypes and phenotype were not completely consistent because of the hypokalemia. This case emphasizes that once a proband is diagnosed with LS by genetic testing, family genetic sequencing is necessary for early diagnosis and intervention for other family members, to protect against severe cardiovascular complications.

scholarly journals A Frameshift Mutation in MC1R and a High Frequency of Somatic Reversions Cause Black Spotting in Pigs

Genetics ◽  
2001 ◽  
Vol 158 (2) ◽  
pp. 779-785 ◽  
Author(s):  
J M H Kijas ◽  
M Moller ◽  
G Plastow ◽  
L Andersson
Keyword(s):  
Frameshift Mutation ◽  
Coat Color ◽  
Stop Codon ◽  
Phenotypic Expression ◽  
Premature Stop Codon ◽  
Black Spot ◽  
White Background ◽  
Coding Region ◽  
Black Spots ◽  
Color Sequence

Abstract Black spotting on a red or white background in pigs is determined by the EP allele at the MC1R/Extension locus. A previous comparison of partial MC1R sequences revealed that EP shares a missense mutation (D121N) with the ED2 allele for dominant black color. Sequence analysis of the entire coding region now reveals a second mutation in the form of a 2-bp insertion at codon 23 (nt67insCC). This mutation expands a tract of six C nucleotides to eight and introduces a premature stop codon at position 56. This frameshift mutation is expected to cause a recessive red color, which was in fact observed in some breeds with the EP allele present (Tamworth and Hereford). RT-PCR analyses were conducted using skin samples taken from both spotted and background areas of spotted pigs. The background red area had transcript only from the mutant nt67insCC MC1R allele, whereas the black spot also contained a transcript without the 2-bp insertion. This indicates that black spots are due to somatic reversion events that restore the frame and MC1R function. The phenotypic expression of the EP allele is highly variable and the associated coat color ranges from red, red with black spots, white with black spots, to almost completely solid black. In several breeds of pigs the phenotypic manifestation of this allele has been modified by selection for or against black spots.

scholarly journals The High-Pathogenicity Island of Yersinia enterocolitica Ye8081 Undergoes Low-Frequency Deletion but Not Precise Excision, Suggesting Recent Stabilization in the Genome

1999 ◽  
Vol 67 (10) ◽  
pp. 5091-5099 ◽  
Author(s):  
Sandrine Bach ◽  
Carmen Buchrieser ◽  
Michael Prentice ◽  
Annie Guiyoule ◽  
Tarek Msadek ◽  
...  
Keyword(s):  
Stop Codon ◽  
Premature Stop Codon ◽  
Low Frequency ◽  
Pathogenicity Island ◽  
Selection Strategy ◽  
Phenotypic Traits ◽  
Uptake System ◽  
Integrase Gene ◽  
Precise Excision ◽  
High Pathogenicity

ABSTRACT Highly pathogenic strains of Yersinia pestis, Y. pseudotuberculosis, and Y. enterocolitica are characterized by the possession of a pathogenicity island designated the high-pathogenicity island (HPI). This 35- to 45-kb island carries an iron uptake system named the yersiniabactin locus. While the HPIs ofY. pestis and Y. pseudotuberculosis are subject to high-frequency spontaneous deletion from the chromosome, we were initially unable to obtain HPI-deleted Y. enterocolitica 1B isolates. In the present study, using a positive selection strategy, we identified three HPI-deleted mutants of Y. enterocoliticastrain Ye8081. In these three independent clones, the chromosomal deletion was not limited to the HPI but encompassed a larger DNA fragment of approximately 140 kb. Loss of this fragment, which occurred at a frequency of approximately 5 × 10−7, resulted in the disappearance of several phenotypic traits, such as growth in a minimal medium, hydrolysis ofo-nitrophenyl-β-d-thiogalactopyranoside, Tween esterase activity, and motility, and in a decreased virulence for mice. However, no precise excision of the Ye8081 HPI was observed. To gain more insight into the molecular basis for this phenomenon, the putative machinery of HPI excision in Y. enterocolitica was analyzed and compared to that in Y. pseudotuberculosis. We show that the probable reasons for failure of precise excision of the HPI of Y. enterocolitica Ye8081 are (i) the interruption of the P4-like integrase gene located close to its right-hand boundary by a premature stop codon and (ii) lack of conservation of 17-bpatt-like sequences at both extremities of the HPI. These mutations may represent a process of HPI stabilization in the speciesY. enterocolitica.

scholarly journals Identification of W13 in the American Miniature Horse and Shetland Pony Populations

Genes ◽  
2021 ◽  
Vol 12 (12) ◽  
pp. 1985
Author(s):  
Elizabeth Esdaile ◽  
Angelica Kallenberg ◽  
Felipe Avila ◽  
Rebecca R. Bellone
Keyword(s):  
Genetic Testing ◽  
Tyrosine Kinase ◽  
Allele Frequency ◽  
Receptor Tyrosine Kinase ◽  
Marker Assisted Selection ◽  
Coat Color ◽  
Low Frequency ◽  
The Other ◽  
Single Individual ◽  
Economic Significance

Coat color is a trait of economic significance in horses. Variants in seven genes have been documented to cause white patterning in horses. Of the 34 variants that have been identified in KIT proto-oncogene, receptor tyrosine kinase (KIT), 27 have only been reported in a single individual or family and thus not all are routinely offered for genetic testing. Therefore, to enable proper use of marker-assisted selection, determining breed specificity for these alleles is warranted. Screening 19 unregistered all-white Shetland ponies for 16 white patterning markers identified 14 individuals whose phenotype could not be explained by testing results. In evaluating other known dominant white variants, 14 horses were heterozygous for W13. W13 was previously only reported in two quarter horses and a family of Australian miniature horses. Genotyping known white spotting variants in 30 owner-reported white animals (25 Miniature Horses and five Shetland ponies) identified two additional W13/N American Miniature Horses. The estimated allele frequency of W13 in the American Miniature Horse was 0.0063 (79 N/N, 1 W13/N) and the allele was not detected in a random sample (n = 59) of Shetland ponies. No homozygous W13 individuals were identified and W13/N ponies had a similar all-white coat with pink skin phenotype, regardless of the other white spotting variants present, demonstrating that W13 results in a Mendelian inherited dominant white phenotype and homozygosity is likely lethal. These findings document the presence of W13 in the American Miniature Horse and Shetland pony populations at a low frequency and illustrate the importance of testing for this variant in additional breeds.

scholarly journals A Stop-Gain Mutation within MLPH Is Responsible for the Lilac Dilution Observed in Jacob Sheep

Genes ◽  
2020 ◽  
Vol 11 (6) ◽  
pp. 618 ◽  
Author(s):  
Christian J. Posbergh ◽  
Elizabeth A. Staiger ◽  
Heather J. Huson
Keyword(s):  
Autosomal Recessive ◽  
Coat Color ◽  
Color Change ◽  
Stop Codon ◽  
Premature Stop Codon ◽  
Autosomal Recessive Inheritance ◽  
Pedigree Analysis ◽  
Causative Mutation ◽  
Nonsynonymous Mutation ◽  
Original Case

A coat color dilution, called lilac, was observed within the Jacob sheep breed. This dilution results in sheep appearing gray, where black would normally occur. Pedigree analysis suggested an autosomal recessive inheritance. Whole-genome sequencing of a dilute case, a known carrier, and sixteen non-dilute sheep was used to identify the molecular variant responsible for the coat color change. Through investigation of the genes MLPH, MYO5A, and RAB27A, we discovered a nonsynonymous mutation within MLPH, which appeared to match the reported autosomal recessive nature of the lilac dilution. This mutation (NC_019458.2:g.3451931C>A) results in a premature stop codon being introduced early in the protein (NP_001139743.1:p.Glu14*), likely losing its function. Validation testing of additional lilac Jacob sheep and known carriers, unrelated to the original case, showed a complete concordance between the mutation and the dilution. This stop-gain mutation is likely the causative mutation for dilution within Jacob sheep.

scholarly journals A sleep modulated Channelopathy: a novel CACNA1A pathogenic variant identified in episodic Ataxia type 2 and a potential link to sleep alleviated migraine

BMC Neurology ◽  
2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Abhimanyu S. Ahuja ◽  
Todd D. Rozen ◽  
Paldeep S. Atwal
Keyword(s):  
Genetic Testing ◽  
Stop Codon ◽  
Premature Stop Codon ◽  
Pathogenic Variant ◽  
Episodic Ataxia ◽  
Case Presentation ◽  
Episodic Ataxia Type 2 ◽  
Potential Link ◽  
Episodic Ataxia Type

Abstract Background To describe a patient with sleep alleviated episodic ataxia type 2 with a novel CACNA1A pathogenic variant and provide a possible link to sleep responsive migraine. Case presentation A 26-year-old woman with recurrent attacks of dizziness, nausea, vomiting, ataxia and dysarthria presented for a possible diagnosis of vestibular migraine. Unique to her attacks was if she could fall asleep for as little as 15 min the spells would subside. If however she remained awake the attacks would continue unabated. A presumed diagnosis of episodic ataxia type 2 was made and she became attack free on acetazolamide without recurrence. Genetic testing demonstrated a novel pathogenic variant in CACNA1A on chromosome 19. This pathogenic variant has not been previously reported in the literature and is suggested to truncate the CACNA1A polypeptide by introducing a premature stop codon. Conclusion A case of episodic ataxia type 2 with a novel pathogenic variant in CACNA1A is described. Interestingly, the patient’s symptoms would completely alleviate with sleep which suggests a sleep modulated channelopathy. The mechanisms by which sleep could potentially alter this pathogenic variant are hypothesized. A potential link to sleep alleviated migraine is suggested. Further study of this novel pathogenic variant may help us understand not only how sleep can modulate episodic ataxia type 2, but also migraine.

scholarly journals Truncated Epithelial Sodium Channel β Subunit Responsible for Liddle Syndrome in a Chinese Family

2019 ◽  
Vol 44 (5) ◽  
pp. 942-949
Author(s):  
Peng Fan ◽  
Chao-Xia Lu ◽  
Kun-Qi Yang ◽  
Pei-Pei Lu ◽  
Su-Fang Hao ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Sodium Channel ◽  
Frameshift Mutation ◽  
Stop Codon ◽  
Premature Stop Codon ◽  
Epithelial Sodium Channel ◽  
Chinese Family ◽  
Liddle Syndrome ◽  
Direct Dna Sequencing ◽  
Py Motif

Background/Aims: Liddle syndrome (LS) is a rare autosomal dominant disease caused by mutations in genes coding for epithelial sodium channel (ENaC) subunits. The aim of this study was to identify the mutation responsible for the LS in an extended Chinese family. Methods: DNA samples from the proband with early-onset, treatment-resistant hypertension, and hypokalemia and 19 additional relatives were all sequenced for mutations in exon 13 of the β-ENaC and γ-ENaC genes, using amplification by polymerase chain reaction and direct DNA sequencing. Results: Genetic testing of exon 13 of SCNN1B revealed duplication of guanine into a string of 3 guanines located at codon 602. This frameshift mutation is predicted to generate a premature stop codon at position 607, resulting in truncated β-ENaC lacking the remaining 34 amino acids, including the crucial PY motif. Among a total of 9 participants with the identical mutation, different phenotypes were identified. Tailored treatment with amiloride was safe and effective in alleviating disease symptoms in LS. No mutation of SCNN1G was identified in any of the examined participants. Conclusions: We report here a family affected by LS harboring a frameshift mutation (c.1806dupG) with a premature stop codon deleting the PY motif of β-ENaC. Our study demonstrates that the earlier LS patients are diagnosed by genetic testing and treated with tailored medication, the greater the likelihood of preventing or minimizing complications in the vasculature and target organs.

scholarly journals Low Frequency of Ceftazidime-Avibactam Resistance among Enterobacteriaceae Isolates Carrying blaKPC Collected in U.S. Hospitals from 2012 to 2015

2016 ◽  
Vol 61 (3) ◽  
Author(s):  
Mariana Castanheira ◽  
Rodrigo E. Mendes ◽  
Helio S. Sader
Keyword(s):  
Efflux Pump ◽  
Stop Codon ◽  
Premature Stop Codon ◽  
Low Frequency ◽  
Resistance Mechanisms ◽  
Sequencing Analysis ◽  
Relative Quantification ◽  
Large Collection ◽  
Icu Patients ◽  
Content Type

ABSTRACT Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacteriaceae isolates have been increasingly reported worldwide, and therapeutic options to treat infections caused by these organisms are limited. We evaluated the activity of ceftazidime-avibactam and comparators against 456 Enterobacteriaceae isolates carrying bla KPC collected from 79 U.S. hospitals during 2012 to 2015. Overall, ceftazidime-avibactam (MIC50/90, 0.5/2 μg/ml; 99.3% susceptible) and tigecycline (MIC50/90, 0.5/1 μg/ml; 98.9% susceptible at ≤2 μg/ml) were the most active agents. Only 80.5% and 59.0% of isolates were susceptible to colistin and amikacin, respectively. All three isolates (0.7%) displaying resistance to ceftazidime-avibactam (K. pneumoniae; MICs, ≥16 μg/ml) were evaluated using whole-genome sequencing analysis and relative quantification of expression levels of porins and efflux pump. Two isolates carried metallo-β-lactamase genes, bla NDM-1 or bla VIM-4, among other β-lactam resistance mechanisms, and one displayed a premature stop codon in ompK35 and decreased expression of ompK36. Ceftazidime-avibactam was active against 100.0 and 99.3% of isolates carrying bla KPC-3 (n = 221) and bla KPC-2 (n = 145), respectively. Isolates carrying bla KPC were more commonly recovered from pneumonia (n = 155), urinary tract (n = 93), and skin/soft tissue (n = 74) infections. Ceftazidime-avibactam (97.8 to 100.0% susceptible) was consistently active against isolates from all infection sites. K. pneumoniae (83.3% of the collection) susceptibility rates were 99.2% for ceftazidime-avibactam, 98.9% for tigecycline, and 80.1% for colistin. Ceftazidime-avibactam susceptibility did not vary substantially when comparing isolates from intensive care unit (ICU) patients to those from non-ICU patients. Ceftazidime-avibactam was active against this large collection of isolates carrying bla KPC and represents a valuable addition to the armamentarium currently available for the treatment of infections caused by KPC-producing Enterobacteriaceae.

Ectopic Transcript Analysis Indicates that Allelic Exclusion is an Important Cause of Type I Protein C Deficiency in Patients with Nonsense and Frameshift Mutations in the PROC Gene

1996 ◽  
Vol 75 (06) ◽  
pp. 870-876 ◽  
Author(s):  
José Manuel Soria ◽  
Lutz-Peter Berg ◽  
Jordi Fontcuberta ◽  
Vijay V Kakkar ◽  
Xavier Estivill ◽  
...  
Keyword(s):  
Splice Site ◽  
Protein C ◽  
Stop Codon ◽  
Premature Stop Codon ◽  
Allelic Exclusion ◽  
Polymorphism Analysis ◽  
Type I ◽  
Protein C Deficiency ◽  
Nonsense Mutations ◽  
Stop Codons

SummaryNonsense mutations, deletions and splice site mutations are a common cause of type I protein C deficiency. Either directly or indirectly by altering the reading frame, these' lesions generate or may generate premature stop codons and could therefore be expected to result in premature termination of translation. In this study, the possibility that such mutations could instead exert their pathological effects at an earlier stage in the expression pathway, through “allelic exclusion” at the RNA level, was investigated. Protein C (PROC) mRNA was analysed in seven Spanish type I protein C deficient patients heterozygous for two nonsense mutations, a 7bp deletion, a 2bp insertion and three splice site mutations. Ectopic RNA transcripts from patient and control lymphocytes were analysed by RT-PCR and direct sequencing of amplified PROC cDNA fragments. The nonsense mutations and the deletion were absent from the cDNAs indicating that only mRNA derived from the normal allele had been expressed. Similarly for the splice site mutations, only normal PROC cDNAs were obtained. In one case, exclusion of the mutated allele could be confirmed by polymorphism analysis. In contrast to these six mutations, the 2 bp insertion was not associated with loss of mRNA from the mutated allele. In this case, cDNA analysis revealed the absence of 19 bases from the PROC mRNA consistent with the generation and utilization of a cryptic splice site 3’ to the site of mutation, which would result in a frameshift and a premature stop codon. It is concluded that allelic exclusion is a common causative mechanism in those cases of type I protein C deficiency which result from mutations that introduce premature stop codons

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