scholarly journals Independent DSG4 frameshift variants in cats with hair shaft dystrophy

2021 ◽  
Author(s):  
Sarah Kiener ◽  
Ana Rostaher ◽  
Silvia Rüfenacht ◽  
Vidhya Jagannathan ◽  
John P. Sundberg ◽  
...  
Keyword(s):  
Domestic Animals ◽  
Hair Shaft ◽  
Complete Loss ◽  
Loss Of Function ◽  
Reading Frame ◽  
Transmembrane Glycoprotein ◽  
Normal Hair ◽  
Spontaneous Mutants ◽  
Hair Shafts ◽  
Keratin Intermediate Filaments

AbstractInvestigations of hereditary phenotypes in spontaneous mutants may help to better understand the physiological functions of the altered genes. We investigated two unrelated domestic shorthair cats with bulbous swellings of the hair shafts. The clinical, histopathological, and ultrastructural features were similar to those in mice with lanceolate hair phenotype caused by loss-of-function variants in Dsg4 encoding desmoglein 4. We sequenced the genomes from both affected cats and compared the data of each affected cat to 61 control genomes. A search for private homozygous variants in the DSG4 candidate gene revealed independent frameshift variants in each case, c.76del or p.Ile26fsLeu*4 in case no. 1 and c.1777del or p.His593Thrfs*23 in case no. 2. DSG4 is a transmembrane glycoprotein located primarily in the extracellular part of desmosomes, a complex of adhesion molecules responsible for connecting the keratin intermediate filaments of neighbouring epithelial cells. Desmosomes are essential for normal hair shaft formation. Both identified DSG4 variants in the affected cats lead to premature stop codons and truncate major parts of the open-reading frame. We assume that this leads to a complete loss of DSG4 function, resulting in an incorrect formation of the desmosomes and causing the development of defective hair shafts. Together with the knowledge on the effects of DSG4 variants in other species, our data suggest that the identified DSG4 variants cause the hair shaft dystrophy. To the best of our knowledge, this study represents the first report of pathogenic DSG4 variants in domestic animals.

scholarly journals Trps1-deficient transplanted skin gave rise to a substantial amount of hair: Trps1 is unnecessary for hair development

2019 ◽  
Vol 11 (1) ◽  
Author(s):  
Yingzhe Zhang ◽  
Tomoyuki Nakamura ◽  
Fukumi Furukawa ◽  
Yasuteru Muragaki
Keyword(s):  
Hair Growth ◽  
Mouse Skin ◽  
Hair Shaft ◽  
Hair Follicles ◽  
Newborn Mouse ◽  
Newborn Mice ◽  
Significant Difference ◽  
Normal Hair ◽  
Hair Development ◽  
Hair Shafts

Trps1 is considered as an important gene involved in the interactions between the epithelial and mesenchymal cells during hair follicle morphogenesis. The number of hair follicles in Trps1 Knockout (KO) newborn mouse skin was significantly lower than that in wild-type (WT) newborn skin. To gain insight into the functional role of Trps1 in hair development, we transplanted Trps1 KO newborn mouse skin on the backs of nude mice and examined hair growth at day 42 after transplantation. Surprisingly, transplanted skin from Trps1 KO newborn mice gave rise to a substantial amount of hair, although the hair was softer than that of WT mice. Histological examination revealed that the diameter of both hair follicles and hair shafts were significantly lower, whereas the density of hair follicles showed no significant difference between the Trps1 KO and WT mice. We introduce mouse hair follicles as a fascinating model to study the functions of Trps1 in mouse hair growth and pathology. This model suggests that the function of Trps1 is unnecessary for the development of normal hair follicles and hair shafts, although the loss of Trps1 affects the diameters of hair follicles and hair shaft.

Chronic Ischemic Monomelic Neuropathy after Arteriovenous Fistula Creation: A Unique Presentation of Vascular Steal

2020 ◽  
Vol 3 (2) ◽  
pp. 147-150
Author(s):  
Kaczynski RE ◽  
Asaad Y ◽  
Valentin-Capeles N ◽  
Battista J
Keyword(s):  
Arteriovenous Fistula ◽  
Complete Loss ◽  
Dialysis Access ◽  
Loss Of Function ◽  
Access Site ◽  
Surgical Ligation ◽  
Arteriovenous Access ◽  
Vascular Steal ◽  
Steal Syndrome

We discuss a case of a 58 year old male who presented for left upper extremity steal syndrome including ischemic monomelic neuropathy (IMN) 1.5 months after arteriovenous fistula creation. He presented after three surgical attempts to salvage his fistula with rest pain, complete loss of function with contracture of the 4th and 5th digits, and loss of sensation in the ulnar distribution for more than three weeks. At our institution, he underwent surgical ligation of the distal fistula and creation of a new fistula proximally, resulting in complete resolution of his vascular steal symptoms almost immediately despite the chronicity prior to surgical presentation. Our patient provides a unique perspective regarding dialysis access salvage versus patient quality of life. The patients’ functional status and pain levels should take precedence over salvage of an arteriovenous access site, and early ligation of the access should be completed prior to chronic IMN development. However, if a patient presents late along the IMN course, we recommend strong consideration of access ligation in order to attempt to regain the full neurovascular function of the extremity as we experienced in our patient.

scholarly journals Molecular characterisation of rare loss-of-function NPAS3 and NPAS4 variants identified in individuals with neurodevelopmental disorders

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Joseph J. Rossi ◽  
Jill A. Rosenfeld ◽  
Katie M. Chan ◽  
Haley Streff ◽  
Victoria Nankivell ◽  
...  
Keyword(s):  
Neurodevelopmental Disorders ◽  
Protein Function ◽  
Transcriptional Activity ◽  
Neurodevelopmental Disorder ◽  
Complete Loss ◽  
Loss Of Function ◽  
Targeted Disruption ◽  
Clinical Exome Sequencing ◽  
Partner Protein ◽  
The Brain

AbstractAberrations in the excitatory/inhibitory balance within the brain have been associated with both intellectual disability (ID) and schizophrenia (SZ). The bHLH-PAS transcription factors NPAS3 and NPAS4 have been implicated in controlling the excitatory/inhibitory balance, and targeted disruption of either gene in mice results in a phenotype resembling ID and SZ. However, there are few human variants in NPAS3 and none in NPAS4 that have been associated with schizophrenia or neurodevelopmental disorders. From a clinical exome sequencing database we identified three NPAS3 variants and four NPAS4 variants that could potentially disrupt protein function in individuals with either developmental delay or ID. The transcriptional activity of the variants when partnered with either ARNT or ARNT2 was assessed by reporter gene activity and it was found that variants which truncated the NPAS3/4 protein resulted in a complete loss of transcriptional activity. The ability of loss-of-function variants to heterodimerise with neuronally enriched partner protein ARNT2 was then determined by co-immunoprecipitation experiments. It was determined that the mechanism for the observed loss of function was the inability of the truncated NPAS3/4 protein to heterodimerise with ARNT2. This further establishes NPAS3 and NPAS4 as candidate neurodevelopmental disorder genes.

scholarly journals Bilateral angiomyolipoma of the kidney in patient with tuberous sclerosis

2005 ◽  
Vol 133 (9-10) ◽  
pp. 433-437
Author(s):  
Radoje Colovic ◽  
Natasa Colovic ◽  
Nikica Grubor ◽  
Vladimir Radak ◽  
Marijan Micev ◽  
...  
Keyword(s):  
Tuberous Sclerosis ◽  
Complete Loss ◽  
Hla Typing ◽  
Uneventful Recovery ◽  
Loss Of Function ◽  
Kidney Tumors ◽  
Benign Nature ◽  
The Right ◽  
Slow Growing

Angiomyolipomas are relatively frequent tumors of the kidney. It is believed that about 10 million people worldwide have such a tumor. About 1/10 of these 10 million are patients who suffer from tuberous sclerosis. The tumors are frequently bilateral, slow growing, and usually a symptomatic, as well as being rare in children. Due to the benign nature of angiomyolipomas, surgical treatment and embolisation of the tumors are generally not recommended, unless renal function is endangered, the symptoms are severe, or the kidney in question becomes completely dysfunctional. This is particularly the case in patients with tuberous sclerosis in whom these tumors are either already bilateral or may become so. We present a 24-year-old woman with tuberous sclerosis in whom bilateral kidney tumors were diagnosed 7 years earlier and in whom we carried out a left nephrectomy of a 5300 gram angiomyolipoma, which caused pain and complete loss of function. Although timorous, the right kidney was functional, so it was left untouched. After an uneventful recovery, a close follow-up was recommended, as well as HLA typing, as it is highly probable that the right kidney will gradually become inadequate or completely dysfunctional, so that haemodialysis and/or kidney transplantation along with nephrectomy will become necessary.

scholarly journals SMARCB1/INI1-deficient tumors of adulthood

F1000Research ◽  
2020 ◽  
Vol 9 ◽  
pp. 662
Author(s):  
Nathaniel A. Parker ◽  
Ammar Al-Obaidi ◽  
Jeremy M. Deutsch
Keyword(s):  
Progressive Disease ◽  
Therapeutic Strategies ◽  
Complete Loss ◽  
Rhabdoid Tumor ◽  
Diverse Group ◽  
Loss Of Function ◽  
Genetic Aberrations ◽  
Mosaic Expression ◽  
Aggressive Tumors ◽  
Rhabdoid Tumors

The SMARCB1/INI1 gene was first discovered in the mid-1990s, and since then it has been revealed that loss of function mutations in this gene result in aggressive rhabdoid tumors. Recently, the term “rhabdoid tumor” has become synonymous with decreased SMARCB1/INI1 expression. When genetic aberrations in the SMARCB1/INI1 gene occur, the result can cause complete loss of expression, decreased expression, and mosaic expression. Although SMARCB1/INI1-deficient tumors are predominantly sarcomas, this is a diverse group of tumors with mixed phenotypes, which can often make the diagnosis challenging. Prognosis for these aggressive tumors is often poor. Moreover, refractory and relapsing progressive disease is common. As a result, accurate and timely diagnosis is imperative. Despite the SMARCB1/INI1 gene itself and its implications in tumorigenesis being discovered over two decades ago, there is a paucity of rhabdoid tumor cases reported in the literature that detail SMARCB1/INI1 expression. Much work remains if we hope to provide additional therapeutic strategies for patients with aggressive SMARCB1/INI1-deficient tumors.

scholarly journals Putty kidney

JMS SKIMS ◽  
2019 ◽  
Vol 22 (2) ◽  
Author(s):  
Arshed Hussain Parry ◽  
Irfan Robbani ◽  
Tariq Ahmad Gojwari
Keyword(s):  
Renal Involvement ◽  
Complete Loss ◽  
Stricture Formation ◽  
Loss Of Function

Renal involvement by tuberculosis leads to fibrosis and multi focal stricturing of calyces with formation of hydrocalyces. The obstructed calyceal system accumulates caseous pus within it which eventually calcifies. This obstructed and calcified kidney is non-functional and is referred to ‘putty kidney’ and this cascade of fibrosis, stricture formation, calcification with complete loss of function is called as autonephrectomy (1,2).

Genetic analysis of laminin A reveals diverse functions during morphogenesis in Drosophila

Development ◽  
1993 ◽  
Vol 118 (2) ◽  
pp. 325-337 ◽  
Author(s):  
C. Henchcliffe ◽  
L. Garcia-Alonso ◽  
J. Tang ◽  
C.S. Goodman
Keyword(s):  
Cell Fate ◽  
Genetic Characterization ◽  
Complete Loss ◽  
Loss Of Function ◽  
Partial Loss ◽  
Multidomain Structure ◽  
A Subunit ◽  
Wing Structure

In order to dissect the functions of laminin A in vivo, we have undertaken a molecular and genetic characterization of the laminin A subunit (lamA) gene in Drosophila. Sequence analysis predicts a multidomain structure similar to mammalian homologs. We generated a series of complete and partial loss-of-function mutant alleles of the lamA gene; complete loss-of-function mutations lead to late embryonic lethality. Certain combinations of partial loss-of-function lamA alleles give rise to escaper adults, which have rough eyes associated with changes in cell fate and pattern, misshapen legs and defects in wing structure. These phenotypes suggest that laminin A has diverse functions during morphogenesis in Drosophila.

scholarly journals Comparative Dispositions of Ofloxacin in Human Head, Axillary, and Pubic Hairs

1998 ◽  
Vol 42 (5) ◽  
pp. 1298-1302 ◽  
Author(s):  
Kazuhiro Kosuge ◽  
Toshihiko Uematsu ◽  
Sei-Ichi Araki ◽  
Hiroyuki Matsuno ◽  
Kyoichi Ohashi ◽  
...  
Keyword(s):  
Growth Rate ◽  
Human Head ◽  
Pubic Hair ◽  
Hair Shaft ◽  
The Other ◽  
Healthy Male ◽  
Head Hair ◽  
Hair Type ◽  
Axillary Hair ◽  
Hair Shafts

ABSTRACT The distribution of ofloxacin (OFLX) along the shaft of each of three hair types, i.e., head, axillary and pubic, was investigated and compared among five healthy male volunteers 1 to 4 months after ingestion of OFLX for 1 or 2 days (total dose, 200 or 600 mg). Five strands of each hair type were sectioned together into successive 0.5-cm lengths starting from the dermal end, over a length of ≤6 cm, and the OFLX concentration in each hair section was measured by high-pressure liquid chromatography with fluorescence detection. The distribution of OFLX along the head hair shaft was narrow, having a single peak even 3 to 4 months after administration, suggesting a rather uniform growth rate among hair strands. On the other hand, the OFLX distribution along axillary or pubic hair shafts tended to be broad, even having two apparent peaks, and the growth rate did not seem uniform. Since axillary hair seemed to stop growing after having gained a length of ≤4 to 5 cm, it was suggested to enter a resting stage after the growth of ≤3 cm over the 2 to 4 months after OFLX incorporation. These findings indicate that head hair is the most suitable for analysis of individual drug use and the larger growth rate and cycle stage variabilities of strands of the other types of hair should be taken into account.

scholarly journals Old gene, new phenotype: splice-altering variants in CEACAM16 cause recessive non-syndromic hearing impairment

2018 ◽  
Vol 55 (8) ◽  
pp. 555-560 ◽  
Author(s):  
Kevin T Booth ◽  
Kimia Kahrizi ◽  
Hossein Najmabadi ◽  
Hela Azaiez ◽  
Richard JH Smith
Keyword(s):  
Hearing Loss ◽  
Hearing Impairment ◽  
Loss Of Function ◽  
Bioinformatics Pipeline ◽  
Exon 2 ◽  
Reading Frame ◽  
Sequencing Platform ◽  
Syndromic Hearing Impairment ◽  
Generation Sequencing

BackgroundHearing loss is a genetically and phenotypically heterogeneous disorder.ObjectivesThe purpose of this study was to determine the genetic cause underlying the postlingual progressive hearing loss in two Iranian families.MethodsWe used OtoSCOPE, a next-generation sequencing platform targeting >150 genes causally linked to deafness, to screen two deaf probands. Data analysis was completed using a custom bioinformatics pipeline, and variants were functionally assessed using minigene splicing assays.ResultsWe identified two homozygous splice-altering variants (c.37G>T and c.662–1G>C) in the CEACAM16 gene, segregating with the deafness in each family. The minigene splicing results revealed the c.37G>T results in complete skipping of exon 2 and loss of the AUG start site. The c.662–1G>C activates a cryptic splice site inside exon 5 resulting in a shift in the mRNA reading frame.ConclusionsThese results suggest that loss-of-function mutations in CEACAM16 result in postlingual progressive hearing impairment and further support the role of CEACAM16 in auditory function.

scholarly journals Mutations in Bartonella bacilliformis gyrB Confer Resistance to Coumermycin A1

1998 ◽  
Vol 42 (11) ◽  
pp. 2906-2913 ◽  
Author(s):  
James M. Battisti ◽  
Laura S. Smitherman ◽  
D. Scott Samuels ◽  
Michael F. Minnick
Keyword(s):  
Amino Acid ◽  
Amino Acid Sequence ◽  
Cell Extract ◽  
Natural Resistance ◽  
Temperature Sensitive ◽  
Bartonella Bacilliformis ◽  
Reading Frame ◽  
E Coli ◽  
Isolation And Characterization ◽  
Spontaneous Mutants

ABSTRACT This study describes the first isolation and characterization of spontaneous mutants conferring natural resistance to an antibiotic for any Bartonella species. The Bartonella bacilliformis gyrB gene, which encodes the B subunit of DNA gyrase, was cloned and sequenced. The gyrB open reading frame (ORF) is 2,079 bp and encodes a deduced amino acid sequence of 692 residues, corresponding to a predicted protein of ∼77.5 kDa. Sequence alignment indicates that B. bacilliformis GyrB is most similar to the GyrB protein from Bacillus subtilis (40.1% amino acid sequence identity) and that it contains the longest N-terminal tail (52 residues) of any GyrB characterized to date. The cloned B. bacilliformis gyrB was expressed in an Escherichia coli S30 cell extract and was able to functionally complement a temperature-sensitive E. coli Cour gyrB mutant (strain N4177). We isolated and characterized spontaneous mutants of B. bacilliformis resistant to coumermycin A1, an antibiotic that targets GyrB. Sequence analysis of gyrB from 12 Cour mutants ofB. bacilliformis identified single nucleotide transitions at three separate loci in the ORF. The predicted amino acid substitutions resulting from these transitions are Gly to Ser at position 124 (Gly124→Ser), Arg184→Gln, and Thr214→Ala or Thr214→Ile, which are analogous to mutated residues found in previously characterized resistant gyrB genes fromBorrelia burgdorferi, E. coli,Staphylococcus aureus, and Haloferax sp. The Cour mutants are three to five times more resistant to coumermycin A1 than the wild-type parental strain.

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