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Abstract Background Axenfeld-Rieger syndrome (ARS) is characterized by bilateral congenital abnormalities of the anterior segment of the eye associated with abnormalities of the teeth, midface, and umbilicus. Most cases of ARS are caused by mutations in the genes encoding PITX2 or FOXC1. Here we describe a family affected by a severe form of ARS. Case presentation Two members of this family (father and daughter) presented with typical ARS and developed severe glaucoma. The ocular phenotype was much more severe in the daughter than in the father. Magnetic resonance imaging (MRI) detected an aggressive form of meningioma in the father. There was no mutation in the PITX2 gene, determined by exon screening. We identified an intragenic deletion by quantitative genomic PCR analysis and characterized this deletion in detail. Conclusion Our findings implicate the first intragenic deletion of the PITX2 gene in the pathogenesis of a severe form of ARS in an affected family. This study stresses the importance of a systematic search for intragenic deletions in families affected by ARS and in sporadic cases for which no mutations in the exons or introns of PITX2 have been found. The molecular genetics of some ARS pedigrees should be re-examined with enzymes that can amplify medium and large genomic fragments.

Abstract Background Ocular albinism type 1 (OA1) is an X-linked ocular disorder characterized by a severe reduction in visual acuity, nystagmus, hypopigmentation of the retinal pigmented epithelium, foveal hypoplasia, macromelanosomes in pigmented skin and eye cells, and misrouting of the optical tracts. This disease is primarily caused by mutations in the OA1 gene. Methods The ophthalmologic phenotype of the patients and their family members was characterized. We screened for mutations in the OA1 gene by direct sequencing of the nine PCR-amplified exons, and for genomic deletions by PCR-amplification of large DNA fragments. Results We sequenced the nine exons of the OA1 gene in 72 individuals and found ten different mutations in seven unrelated families and three sporadic cases. The ten mutations include an amino acid substitution and a premature stop codon previously reported by our team, and eight previously unidentified mutations: three amino acid substitutions, a duplication, a deletion, an insertion and two splice-site mutations. The use of a novel Taq polymerase enabled us to amplify large genomic fragments covering the OA1 gene. and to detect very likely six distinct large deletions. Furthermore, we were able to confirm that there was no deletion in twenty one patients where no mutation had been found. Conclusion The identified mutations affect highly conserved amino acids, cause frameshifts or alternative splicing, thus affecting folding of the OA1 G protein coupled receptor, interactions of OA1 with its G protein and/or binding with its ligand.

Purpose Monogenic diseases until recently appeared simple from a molecular genetics point of view but correlations between genotypes and phenotypes still remain difficult to establish in many diseases and for many genes. For autosomal dominant diseases such as Best Vitelliform Macular Dystrophy, supposed to be a juvenile disease, it appears that mutations of BEST1 gene can cause multiple phenotypes including early onset and late onset phenotypes as well as unexpected phenotypes such as RP. We report several novel mutations and their associated phenotypes and describe phenotypes linked to previously reoported mutations for which the phenotype had not been describe at all previously. The role of SOX9, MITF and OTX2 in the incomplete penetrance and the variable expressivity of BVMDs is duscussed as well the potential roles of SNPs occuring in coding exons Methods We used genomic PCR with appropriate primers flanking all the exons of the BEST1 gene in order to amplify them. This Genomic PCR was followed by automated sequencing and careful analysis of the sequences obtained. Results We report the case of an unusual family where the Mother II2 of the proband III1, his maternal aunt II3, his brother III3 and his first cousin IIIIV, the son of his maternal aunt, carry a missense mutatation causing apparently only electrophysiological abnormalities. The Father II1 of the proband III1 turned out to carry a stop codon instead of the fifth normal BEST1 codon. The father did not display any electrophysiological nor any clinical abnormality and has a perfect monocular and binocular vision. In contrast the proband III1 carries both mutations with a severe phenotype. Conclusion This report exemplifies the necessity to study all family members in the case of BVMDs. [ABSTRACT FROM AUTHOR]

A correction to the article "A Gene Transfer Comparative Study of HSA-Conjugated Antiangiogenic Factors in a Transgenic Mouse Model of Metastatic Ocular Cancer" that was published in the previous issue is presented.

We present a technique for increasing the internal quality factor of kinetic inductance detectors (KIDs) by nulling ambient magnetic fields with a properly applied magnetic field. The KIDs used in this study are made from thin-film aluminum, they are mounted inside a light-tight package made from bulk aluminum, and they are operated near 150 mK. Since the thin-film aluminum has a slightly elevated critical temperature (Tc=1.4 K), it therefore transitions before the package (Tc=1.2 K), which also serves as a magnetic shield. On cooldown, ambient magnetic fields as small as approximately 30 μT can produce vortices in the thin-film aluminum as it transitions because the bulk aluminum package has not yet transitioned and therefore is not yet shielding. These vortices become trapped inside the aluminum package below 1.2K and ultimately produce low internal quality factors in the thin-film superconducting resonators. We show that by controlling the strength of the magnetic field present when the thin film transitions, we can control the internal quality factor of the resonators. We also compare the noise performance with and without vortices present, and find no evidence for excess noise beyond the increase in amplifier noise, which is expected with increasing loss. [ABSTRACT FROM AUTHOR]

Summary: Golden cats have been appreciated since the beginning of the cat fancy. Golden is a modification of the tabby coat. In the Siberian breed, a specific golden phenotype, named sunshine, has been described. Sunshine tabby cats exhibit a warm tone of tabby, a pink nose lacking the black lining and a large light cream area around the nose. Pedigree analyses revealed an autosomal recessive inheritance pattern. A single candidate region was identified by genome‐wide association study (GWAS) and homozygosity mapping. Within that region, we identified CORIN (Corin, serine peptidase) as a strong candidate gene, since CORIN variants have been identified in mice and tigers with a golden phenotype and CORIN has been described as a modifier of the ASIP (Agouti Signaling Protein) pathway. A homozygous CORIN:c.2383C>T missense variant was identified in sunshine tabby cats. Segregation of the variant was consistent with recessive inheritance. The variant was also found in three Kurilian bobtail cats and in two ToyBob cats from the 99 Lives dataset but genotyping of 106 cats from 13 breeds failed to identify carriers in cats from other breeds. The CORIN:c.2383C>T variant was predicted to change an arginine to a cysteine at position 795 in the protein: CORIN:p.(Arg795Cys). Finally, hair observation in Siberian cats was consistent with elongated ASIP signaling as golden hair showed a large yellow band instead of the short subapical one usually observed in agouti hair. These results support an association of the Siberian sunshine modification with the CORIN:c.2383C>T variant. The Siberian cat has helped us to decipher one of the golden phenotypes observed in cats and we propose that the CORIN:c.2383C>T variant represents the wbSIB (Siberian recessive wideband) allele in the domestic cat. [ABSTRACT FROM AUTHOR]

Muller glial cells (MGC) are essential for normal functioning of retina. They are especially involved in potassium (K+) and water homeostasis, via inwardly rectifying K+ (Kir 4.1) and aquaporin-4 (AQP4) channels respectively. Because MGC appear morphologically and functionally altered in most retinal pathologies, we studied the expression of AQP 4 and Kir 4.1 during the time course of progressive retinal degeneration in Royal College of Surgeons (RCS) rats, an animal model for the hereditary human retinal degenerative disease Retinitis pigmentosa . Simultaneous detection of AQP4 and Kir 4.1 was performed by quantitative real-time polymerase chain reaction (QRT-PCR), Western blot and immunohistochemistry at birth and during progression of the pathology. Although small quantities of AQP4 and Kir 4.1 mRNA were detected at birth (postnatal day (PNd) 0) in both control and dystrophic rat retinas, proteins could not be detected at this age. Detectable proteins appeared in the second week of postnatal life. From PNd15 onwards, the time course in the expression of both AQP4 and Kir 4.1 mRNAs and protein was similar in dystrophic and control rats, with a progressive increase peaking at PNd60 and a subsequent decrease by one year. AQP4 protein and mRNA content were significantly lowered in dystrophic compared to control rats. Kir 4.1 protein levels were also lower in dystrophic retinas, while mRNA concentrations were unchanged and/or slightly higher in dystrophic rats. The discrepancies between Kir4.1 mRNA and protein suggest perturbation in protein translation due to the pathology. AQP4 and Kir 4.1/vimentin co-immunolabeling showed that: 1) apical radial processes of some MGC invaded the subretinal zone, and 2) MGC morphology was distorted in advanced pathology. MGC became hypertrophic both during the pathology and also with age in control rats. In conclusion, our results confirm that this inherited photoreceptor degeneration also leads to progressive alterations in physiological and morphological parameters of MGC which may aggravate retinal impairment. [ABSTRACT FROM AUTHOR]

We report photon-noise limited performance of horn-coupled, aluminum lumped-element kinetic inductance detectors at millimeter wavelengths. The detectors are illuminated by a millimeterwave source that uses an active multiplier chain to produce radiation between 140 and 160 GHz. We feed the multiplier with either amplified broadband noise or a continuous-wave tone from a microwave signal generator. We demonstrate that the detector response over a 40 dB range of source power is well-described by a simple model that considers the number of quasiparticles. The detector noise-equivalent power (NEP) is dominated by photon noise when the absorbed power is greater than approximately 1 pW, which corresponds to NEP ≈ 2 × 10–17WHz–1/2, referenced to absorbed power. At higher source power levels, we observe the relationships between noise and power expected from the photon statistics of the source signal: NEP ∝ P for broadband (chaotic) illumination and NEP ∝ P1/2 for continuous-wave (coherent) illumination. [ABSTRACT FROM AUTHOR]

Abstract: Objective. – Percutaneous drainage of pelvic abscesses may be challenging using a conventional anterior route because of overlying intestinal or vascular structures. Although, the posterior transgluteal route is not commonly performed, it may provide a safer approach when the conventional anterior route is not feasible. We retrospectively analyzed our experience in transgluteal percutaneous drainage of pelvic abscesses in 21 patients to determine the feasibility, safety, tolerance and efficacy of this technique. Methods. – The data of 21 patients with pelvic abscesses (15 postoperative and 6 secondary to diverticulitis) who were treated by CT-guided percutaneous transgluteal drainage between 1992 and 2002 were reviewed. Transgluteal drainage was considered as failure in case of persisting clinical sepsis, recurrence of abscess or when surgery was needed. Results. – The procedure was well tolerated in all patients. No major complication was observed. In one patient mild hematoma of the piriform muscle was noticed on postprocedure CT scan but did not require a specific treatment. Successful drainage as documented by follow-up CT examination was observed in 20 patients (20/21; 95%). One case of recurrence which was successfully treated by repeated percutaneous transgluteal drainage was observed in our series. Conclusion. – Percutaneous imaging-guided transgluteal drainage is a feasible, safe, well-tolerated and effective method for the treatment of pelvic abscess when a conventional anterior route is not feasible. [Copyright &y& Elsevier]

The present work studies the effects of a replication-deficient adenovirus (Ad), Ad-RSVbFGF, bearing the human basic fibroblast growth factor (bFGF) cDNA, as a potential vector for therapeutic angiogenesis of ischemic diseases. The different isoforms of the protein were expressed from the viral vector in various cell types and, although the cytoplasmic isoform does not possess a signal peptide, we observed its release from a muscle cell line. The proteins were fully functional when tested in a long-term survival assay of quiescent fibroblasts. After endothelial cell infection with Ad-RSVbFGF, we observed an 80% increase in the mean length of the capillary-like tubes that differentiated in a three-dimensional model of angiogenesis. We evaluated angiogenesis directly in mice 14 days after subcutaneous injection of Matrigel plugs containing Ad-RSVbFGF. A marked neovascularization was observed in the Matrigel plugs and in the surrounding tissues. Finally, the recombinant virus was injected into the hindlimb muscles of mdx mice. A 2.5-fold increase in bFGF content of the muscle was observed 6 days after injection, without any significant variations detected in the animal sera. Immunohistological detection showed an increased number of large-caliber vessels in the treated muscles as compared with control muscles. These results demonstrate that Ad-mediated transfer of the human bFGF gene can induce angiogenesis in muscle, making this tissue a potential target for the treatment of ischemic diseases. [ABSTRACT FROM AUTHOR]

This study investigated the dominant blue eyes (DBE) trait linked to hearing impairment and variable white spotting in Maine Coon cats. Fifty-eight animals descending from 2 different DBE lineages, the Dutch and the Topaz lines, were sampled. They comprised 48 cats from the Dutch bloodline, including 9 green-eyed and 31 blue-eyed cats, with some individuals exhibiting signs of deafness, and 8 stillborn kittens. Samples from the Topaz lineage included 10 blue-eyed animals. A brainstem auditory evoked response test revealed a reduced to absent response to auditory stimuli and absent physiological waveforms in all of the 8 examined DBE animals. We sequenced the genome of 2 affected cats from the Dutch line and searched for variants in 19 candidate genes for the human Waardenburg syndrome and pigmentary disorders. This search yielded 9 private protein-changing candidate variants in the genes PAX3, EDN3, KIT, OCA2, SLC24A5, HERC2, and TYRP1. The genotype-phenotype cosegregation was observed for the PAX3 variant within all animals from the Dutch lineage. The mutant allele was absent from 461 control genomes and 241 additionally genotyped green-eyed Maine Coons. We considered the PAX3 variant as the most plausible candidate-a heterozygous nonsense single base pair substitution in exon 6 of PAX3 (NC_051841.1:g.205,787,310G>A, XM_019838731.3:c.937C>T, XP_019694290.1:p.Gln313*), predicted to result in a premature stop codon. PAX3 variants cause auditory-pigmentary syndrome in humans, horses, and mice. Together with the comparative data from other species, our findings strongly suggest PAX3:c.937C>T (OMIA:001688-9685) as the most likely candidate variant for the DBE, deafness, and minimal white spotting in the Maine Coon Dutch line. Finally, we propose the designation of DBERE (Rociri Elvis Dominant Blue Eyes) allele in the domestic cat., Competing Interests: Conflicts of interest GRG and KS are affiliated with commercial laboratories offering genetic testing for domestic animals. The other authors declare no conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Genetics Society of America.)

During the last 60 years many inherited traits in domestic outbred cats were selected and retained giving birth to new breeds characterised by singular coat or morphological phenotypes. Among them, minimal white spotting associated with blue eyes was selected by feline breeders to create the Altai, Topaz, and Celestial breeds. Various established breeds also introduced this trait in their lineages. The trait, that was confirmed as autosomal dominant by breeding data, was first described in domestic cats from Kazakhstan and Russia, in British shorthair and British longhair from Russia, and in Maine Coon cats from the Netherlands, suggesting different founding effects. Using a genome-wide association study we identified a single region on chromosome C1 that was associated with the minimal white spotting and blue eyes phenotype (also called DBE by breeders for dominant blue eyes) in the French Celestial breed. Within that region we identified Paired Box 3 (PAX3) as the strongest candidate gene, since PAX3 is a key regulator of MITF (Melanocyte-Inducing Transcription Factor) and PAX3 variants have been previously identified in various species showing white spotting with or without blue eyes including the mouse and the horse. Whole genome sequencing of a Celestial cat revealed an endogenous retrovirus LTR (long terminal repeat) insertion within PAX3 intron 4 known to contain regulatory sequences (conserved non-coding element [CNE]) involved in PAX3 expression. The insertion is in the vicinity of CNE2 and CNE3. All 52 Celestial and Celestial-mixed cats with a DBE phenotype presented the insertion, that was absent in their 22 non-DBE littermates and in 87 non-DBE cats from various breeds. The outbred Celestial founder was also heterozygous for the insertion. Additionally, the variant was found in nine DBE Maine Coon cats related to the Celestial founder and four DBE Siberian cats with an uncertain origin. Segregation of the variant in the Celestial breed is consistent with dominant inheritance and does not appear to be associated with deafness. We propose that this NC_018730.3:g.206974029_206974030insN[395] variant represents the DBE CEL (Celestial Dominant Blue Eyes) allele in the domestic cat., (© 2024 The Authors. Animal Genetics published by John Wiley & Sons Ltd on behalf of Stichting International Foundation for Animal Genetics.)

During the last twenty years, minimal white spotting associated with blue eyes was selected by feline breeders to create the Altai, Topaz, and Celestial breeds. Additionally, certain breeders introduced this trait in their lineages of purebred cats. The trait has been called "dominant blue eyes (DBE)" and was confirmed to be autosomal dominant in all lineages. DBE was initially described in outbred cats from Kazakhstan and Russia and in two purebred lineages of British cats from Russia, as well as in Dutch Maine Coon cats, suggesting different founding effects. We have previously identified two variants in the Paired Box 3 (PAX3) gene associated with DBE in Maine Coon and Celestial cats; however, the presence of an underlying variant remains undetermined in other DBE breeding lines. Using a genome-wide association study, we identified a single region on chromosome C1 that was associated with DBE in British cats. Within that region, we identified PAX3 as the strongest candidate gene. Whole-genome sequencing of a DBE cat revealed an RD-114 retrovirus LTR (long terminal repeat) insertion within PAX3 intron 4 (namely NC_018730.3:g.206975776_206975777insN[433]) known to contain regulatory sequences. Using a panel of 117 DBE cats, we showed that this variant was fully associated with DBE in two British lineages, in Altai cats, and in some other DBE lineages. We propose that this NC_018730.3:g.206975776_206975777insN[433] variant represents the DBE ALT ( Altai Dominant Blue Eye ) allele in the domestic cat. Finally, we genotyped DBE cats from 14 lineages for the three PAX3 variants and showed that they were not present in four lineages, confirming genetic heterogeneity of the DBE trait in the domestic cat., Competing Interests: The authors declare that they have no competing interests. Antagene and Generatio are for-profit societies selling DNA tests for animals. The funders had no role in the design of the study; in the collection, analyses, or interpretation of the data; in the writing of the manuscript; or in the decision to publish the results.

Introduction: The correct labeling of a genetic variant as pathogenic is important as breeding decisions based on incorrect DNA tests can lead to the unwarranted exclusion of animals, potentially compromising the long-term health of a population. In human medicine, the American college of Medical Genetics (ACMG) guidelines provide a framework for variant classification. This study aims to apply these guidelines to six genetic variants associated with hypertrophic cardiomyopathy (HCM) in certain cat breeds and to propose a modified criterion for variant classification., Methods: Genetic samples were sourced from five cat breeds: Maine Coon, Sphynx, Ragdoll, Devon Rex, and British Short- and Longhair. Allele frequencies were determined, and in the subset with phenotypes available, odds ratios to determine the association with HCM were calculated. In silico evaluation followed with joint evidence and data from other publications assisting in the classification of each variant., Results: Two variants, MYBPC3:c.91G > C [A31P] and MYBPC3:c.2453C > T [R818W], were designated as pathogenic. One variant, MYH7:c.5647G > A [E1883K], was found likely pathogenic, while the remaining three were labeled as variants of unknown significance., Discussion: Routine genetic testing is advised solely for the MYBPC3:c.91G > C [A31P] in the Maine Coon and MYBPC3:c.2453C > T [R818W] in the Ragdoll breed. The human ACMG guidelines serve as a suitable foundational tool to ascertain which variants to include; however, refining them for application in veterinary medicine might be beneficial., Competing Interests: HA and SD are current and former employees of Wisdom Panel Mars Petcare Science & Diagnostics that offers canine and feline DNA testing as a commercial service. CC is a current employee of Antagene, a DNA testing and genetic analysis company for dogs, cats, horses, and wildlife. MT is employed by Genefast srl. LL has historically received funding from various commercial testing laboratories to support variant discovery but has no involvement with these HCM variants. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Boeykens, Abitbol, Anderson, Dargar, Ferrari, Fox, Hayward, Häggström, Davison, Kittleson, van Steenbeek, Ljungvall, Lyons, Longeri, Ohlsson, Peelman, Dufaure de Citres, Smets, Turba and Broeckx.)

Congenital coat-colour-related deafness is common among certain canine breeds especially those exhibiting extreme white spotting or merle patterning. We identified a non-syndromic deafness in Beauceron dogs characterised by a bilateral hearing loss in puppies that is not linked to coat colour. Pedigree analysis suggested an autosomal recessive transmission. By combining homozygosity mapping with whole genome sequencing and variant filtering in affected dogs we identified a CDH23:c.700C>T variant. The variant, located in the CHD23 (cadherin related 23) gene, was predicted to induce a CDH23:p.(Pro234Ser) change in the protein. Proline-234 of CDH23 protein is highly conserved across different vertebrate species. In silico tools predicted the CDH23:p.(Pro234Ser) change to be deleterious. CDH23 encodes a calcium-dependent transmembrane glycoprotein localised near the tips of hair-cell stereocilia in the mammalian inner ear. Intact function of these cilia is mandatory for the transformation of the acoustical wave into a neurological signal, leading to sensorineural deafness when impaired. By genotyping a cohort of 90 control Beauceron dogs sampled in France, we found a 3.3% carrier frequency. The CDH23:c.[700C>T] allele is easily detectable with a genetic test to avoid at-risk matings., (© 2022 The Authors. Animal Genetics published by John Wiley & Sons Ltd on behalf of Stichting International Foundation for Animal Genetics.)

Background : The prognostic significance of pulmonary venous (PV) flow reversal in degenerative mitral regurgitation (dMR) is not well-established. Objective : We aimed to assess whether reversed PV flow is associated with adverse outcomes in patients with significant dMR. Methods : We retrospectively analyzed consecutive patients referred to a tertiary center for evaluation of dMR of greater than moderate degree, who had normal sinus rhythm, had a left ventricular ejection fraction of above 60%, and did not suffer from any other major valvular disorders. The primary outcome was the combined rate of all-cause mortality, mitral intervention, or new-onset atrial fibrillation (AF) at 5 years following index echocardiogram. Secondary outcomes included individual components of the primary outcome. Results : Overall, 135 patients (median age 68 (IQR, 58-74) years; 93 (68.9%) males; 89 (65.9%) with severe MR) met the inclusion criteria and were followed for 115.2 (IQR, 60.0-155.0) months. Patients with a reversed PV flow pattern (PVFP) (n = 34) more often presented with severe MR compared to those with a normal (n = 49) and non-reversed PVFP (n = 101) (RR = 2.03 and 1.59, respectively, all p < 0.001). At 5 years, they experienced the highest cumulative incidence of the primary outcome (80.2% vs. 59.2% and 67.3%, p = 0.008 and 0.018, respectively). Furthermore, a reversed PVFP was independently associated with a higher risk of the primary outcome compared to normal PVFP (HR 2.53, 95% CI 1.21-5.31, p = 0.011) and non-reversed PVFP (HR 2.14, 95% CI 1.12-4.10, p = 0.022). Conclusion: PV flow reversal is associated with a worse 5-year composite of mortality, mitral intervention, or AF in patients with significant dMR.

Background : Persistent symptoms affect a subset of coronavirus disease 2019 (COVID-19) survivors. Some of these may be cardiovascular (CV)-related. Objective : To assess the burden of objective CV morbidity among, and to explore the short-term course experienced by, COVID-19 patients with post-infectious symptomatology suspected as CV. Methods : This was a single-center, retrospective analysis of consecutive adult patients with new-onset symptoms believed to be CV following recovery from COVID-19, who had been assessed at a dedicated 'Cardio'-COVID clinic between June 2020 and June 2021. All participants were followed for 1 year for symptomatic course and the occurrence of new CV diagnoses and major adverse cardiovascular events (MACE). Results : A total of 96 patients (median age 54 (IQR, 44-64) years, 52 (54%) females) were included in the final analysis. Initial visits occurred within a median of 142 days after the diagnosis of acute COVID. Nearly all (99%) patients experienced a symptomatic acute illness, which was graded as severe in 26 (27%) cases according to the National Institutes of Health (NIH) criteria. Long-COVID symptoms included mainly dyspnea and fatigue. While the initial work-up was mostly normal, 45% of the 11 cardiac magnetic resonance studies performed revealed pathologies. New CV diagnoses were made in nine (9%) patients and mainly included myocarditis that later resolved. An abnormal spirometry was the only variable associated with these. No MACE were recorded. Fifty-two (54%) participants felt that their symptoms improved. No association was found between CV morbidity and symptomatic course. Conclusions : In our experience, long-COVID symptoms of presumed CV origin signified actual CV disease in a minority of patients who, irrespective of the final diagnosis, faced a fair 1-year prognosis.

In the British feline breed a golden coat modification, called light-gold, akita or copper, was reported by breeders during the 2010s. This modification restricted eumelanin to the tip of the tail and hairs showed a wideband modification. Pedigree analyses revealed an autosomal recessive inheritance pattern. A single candidate region was identified using a genome-wide association study. Within that region, we identified CORIN (Corin, serine peptidase) as the strongest candidate gene, since two CORIN variants have previously been identified in Siberian cats with a golden phenotype. A homozygous CORIN:c.2425C>T nonsense variant was identified in copper British cats. Segregation of the variant was consistent with recessive inheritance. This nonsense CORIN:c.2425C>T variant, located in CORIN exon 19, was predicted to produce a truncated CORIN protein - CORIN:p.(Arg809Ter) - that would lack part of the scavenger receptor domain and the trypsine-like serine protease catalytic domain. All 30 copper cats were T/T homozygous for the variant, which was also found in 20 C/T heterozygous British control cats but was absent in 340 cats from the 99 Lives dataset. Finally, genotyping of 218 cats from 12 breeds failed to identify carriers in cats from other breeds. We propose that this third CORIN:c.2425C>T variant represents the wb BSH (British recessive wideband) allele in the domestic cat., (© 2022 The Authors. Animal Genetics published by John Wiley & Sons Ltd on behalf of Stichting International Foundation for Animal Genetics.)

Hereditary ataxias are common among canine breeds with various molecular etiology. We identified a hereditary ataxia in young-adult Australian Shepherd dogs characterized by uncoordinated movements and spasticity, worsening progressively and leading to inability to walk. Pedigree analysis suggested an autosomal recessive transmission. By whole genome sequencing and variant filtering of an affected dog we identified a PNPLA8:c.1169&#95;1170dupTT variant. This variant, located in PNPLA8 (Patatin Like Phospholipase Domain Containing 8), was predicted to induce a PNPLA8:p.(His391PhefsTer394) frameshift, leading to a premature stop codon in the protein. The truncated protein was predicted to lack the functional patatin catalytic domain of PNPLA8, a calcium-independent phospholipase. PNPLA8 is known to be essential for maintaining mitochondrial energy production through tailoring mitochondrial membrane lipid metabolism and composition. The Australian Shepherd ataxia shares molecular and clinical features with Weaver syndrome in cattle and the mitochondrial-related neurodegeneration associated with PNPLA8 loss-of-function variants in humans. By genotyping a cohort of 85 control Australian Shepherd dogs sampled in France, we found a 4.7% carrier frequency. The PNPLA8:c.[1169&#95;1170dupTT] allele is easily detectable with a genetic test to avoid at-risk matings., (© 2022 The Authors. Animal Genetics published by John Wiley & Sons Ltd on behalf of Stichting International Foundation for Animal Genetics.)

Cardiovascular disease remains the leading cause of death among women nowadays. However, there is a persistent lack of awareness of the impact of different risk factors on women's cardiovascular health, in specific pregnancy-related complications, hormonal changes, and psychological aspects. Moreover, there is still not enough awareness of the importance of coronary artery disease (CAD) in women, which leads to a delay in the diagnosis and prompt treatment, particularly during emergent coronary scenarios. Although guidelines suggest the same treatment for women and men who present with acute coronary syndrome (ACS), women are still undertreated. Contemporary data show an improvement over time in the management of ACS in women, however, women are still less likely than men to receive revascularization and pharmacological treatments. Women have higher rates of complications and mortality, in particular the young population, in which all outcomes are still worse in women compared to men. In this review, we aim to emphasize the importance of women's risk factors, women-specific pathophysiology, and clinical presentation in the setting of ACS. This is a review of current challenges in the diagnosis and treatment of women with ACS.

Background: Pre-procedural TIMI coronary flow grade in patients with ST segment elevation myocardial infarction (STEMI) is associated with adverse clinical outcomes. There have been great advances in pharmacologic and invasive treatment of STEMI patients in the current era. We aimed to assess the temporal trends in clinical outcomes according to the TIMI flow grade amongst these patients., Methods: Data of patients with STEMI from the acute coronary syndrome Israeli Survey (ACSIS) registry. A time-dependent analysis stratifying patient by TIMI flow grade 0 and TIMI flow grade 1-3 was performed. Survey years were divided to early (2008-2010) and late period (2013-2018). Clinical outcomes included in-hospital complications, 30d MACE (death, myocardial infarction, stroke, unstable angina, stent thrombosis, urgent revascularization) and 1-year mortality.Results and Conclusions: Included were 2453 patients. The majority of patients had pre-procedural TIMI flow 0 (58.9% in the early period and 58.7% in the late period, P = 0.97). In-hospital complications of patients with TIMI flow 0 has significantly decreased over time (36.1% vs 26.8%, P < 0.001) but not amongst patients with TIMI flow 1-3. Compared with TIMI flow 1-3, patients with TIMI flow 0 had worse 30d MACE and 1-year mortality. There was no temporal change of these outcomes in either TIMI flow grade group. TIMI flow grade 0 is still more common among patients with STEMI and is associated with poorer prognosis. Nevertheless, over time, in-hospital complications have decreased among patients with TIMI 0, while 30d MACE and 1-year mortality has remained unchanged., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Authors.)

Skeletal muscles are composed of hundreds of multinucleated muscle fibers (myofibers) whose myonuclei are regularly positioned all along the myofiber's periphery except the few ones clustered underneath the neuromuscular junction (NMJ) at the synaptic zone. This precise myonuclei organization is altered in different types of muscle disease, including centronuclear myopathies (CNMs). However, the molecular machinery regulating myonuclei position and organization in mature myofibers remains largely unknown. Conversely, it is also unclear how peripheral myonuclei positioning is lost in the related muscle diseases. Here, we describe the microtubule-associated protein, MACF1, as an essential and evolutionary conserved regulator of myonuclei positioning and maintenance, in cultured mammalian myotubes, in Drosophila muscle, and in adult mammalian muscle using a conditional muscle-specific knockout mouse model. In vitro, we show that MACF1 controls microtubules dynamics and contributes to microtubule stabilization during myofiber's maturation. In addition, we demonstrate that MACF1 regulates the microtubules density specifically around myonuclei, and, as a consequence, governs myonuclei motion. Our in vivo studies show that MACF1 deficiency is associated with alteration of extra-synaptic myonuclei positioning and microtubules network organization, both preceding NMJ fragmentation. Accordingly, MACF1 deficiency results in reduced muscle excitability and disorganized triads, leaving voltage-activated sarcoplasmic reticulum Ca 2+ release and maximal muscle force unchanged. Finally, adult MACF1-KO mice present an improved resistance to fatigue correlated with a strong increase in mitochondria biogenesis., Competing Interests: AG, EC, AG, NC, MA, VR, EG, CJ, CS, LL, CS, FJ, VJ, JT, ML, JC, JG, LS, VG No competing interests declared, (© 2021, Ghasemizadeh et al.)

Objectives: Polydactyly has been described in two breeds of domestic cats (Maine Coon and Pixie Bob) and in some outbred domestic cats (eg, Hemingway cats). In most cases, feline polydactyly is a non-syndromic preaxial polydactyly. Three variants located in a regulatory sequence involved in limb development, named ZRS (zone of polarising activity regulatory sequence), have been identified to be responsible for feline polydactyly. These variants have been found in outbred domestic cats in the UK ( UK1 and UK2 variants) and in Hemingway cats in the USA ( Hw variant). The aim of this study was to characterise the genetic features of polydactyly in Maine Coon cats., Methods: Genotyping assay was used to identify the variant(s) segregating in a cohort of 75 polydactyl and non-polydactyl Maine Coon cats from different breeding lines from Europe, Canada and the USA. The authors performed a segregation analysis to identify the inheritance pattern of polydactyly in this cohort and analysed the population structure., Results: The Hw allele was identified in a subset of polydactyl cats. Sequencing of two regulatory sequences involved in limb development did not reveal any other variant in polydactyl cats lacking the Hw allele. Additionally, genotype-phenotype and segregation analyses revealed the peculiar inheritance pattern of polydactyly in Maine Coon cats. The population structure analysis demonstrated a genetic distinction between Hw and Hw -free polydactyl cats., Conclusions and Relevance: Polydactyly in Maine Coon cats is inherited as an autosomal dominant trait with incomplete penetrance and variable expressivity, and this trait is characterised by genetic heterogeneity in the Maine Coon breed. Maine Coon breeders should be aware of this situation and adapt their breeding practices accordingly.

In the feline Donskoy breed, a phenotype that breeders call "pink-eye," with associated light-brown skin, yellow irises and red-eye effect, has been described. Genealogical data indicated an autosomal recessive inheritance pattern. A single candidate region was identified by genome-wide association study and SNP-based homozygosity mapping. Within that region, we further identified HPS5 (HPS5 Biogenesis Of Lysosomal Organelles Complex 2 Subunit 2) as a strong candidate gene, since HPS5 variants have been identified in humans and animals with Hermansky-Pudlak syndrome 5 or oculocutaneous albinism. A homozygous c.2571-1G>A acceptor splice-site variant located in intron 16 of HPS5 was identified in pink-eye cats. Segregation of the variant was 100% consistent with the inheritance pattern. Genotyping of 170 cats from 19 breeds failed to identify a single carrier in non-Donskoy cats. The c.2571-1G>A variant leads to HPS5 exon-16 splicing that is predicted to produce a 52 amino acids in-frame deletion in the protein. These results support an association of the pink-eye phenotype with the c.2571-1G>A variant. The pink-eye Donskoy cat extends the panel of reported HPS5 variants and offers an opportunity for in-depth exploration of the phenotypic consequences of a new HPS5 variant., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

In dogs and cats, unusual coat colour phenotypes may result from various phenomena, including chimerism. In the domestic cat, the tortoiseshell coat colour that combines red and non-red hairs is the most obvious way to identify chimeras in males. Several cases of tortoiseshell males have been reported, some of which were diagnosed as chimeras without any molecular confirmation. Here, we report the case of a female feline chimera identified thanks to its coat colour and confirmed through DNA profiling and a coat colour test. We ruled out the hypothesis of mosaicism and aneuploidy. All the data were consistent with a natural case of female chimerism., (© 2020 Stichting International Foundation for Animal Genetics.)

A variety of cat breeds have been developed via novelty selection on aesthetic, dermatological traits, such as coat colors and fur types. A recently developed breed, the lykoi (a.k.a. werewolf cat), was bred from cats with a sparse hair coat with roaning, implying full color and all white hairs. The lykoi phenotype is a form of hypotrichia, presenting as a significant reduction in the average numbers of follicles per hair follicle group as compared to domestic shorthair cats, a mild to severe perifollicular to mural lymphocytic infiltration in 77% of observed hair follicle groups, and the follicles are often miniaturized, dilated, and dysplastic. Whole genome sequencing was conducted on a single lykoi cat that was a cross between two independently ascertained lineages. Comparison to the 99 Lives dataset of 194 non-lykoi cats suggested two variants in the cat homolog for Hairless (HR) (HR lysine demethylase and nuclear receptor corepressor ) as candidate causal gene variants. The lykoi cat was a compound heterozygote for two loss of function variants in HR, an exon 3 c.1255&#95;1256dupGT (chrB1:36040783), which should produce a stop codon at amino acid 420 (p.Gln420Serfs*100) and, an exon 18 c.3389insGACA (chrB1:36051555), which should produce a stop codon at amino acid position 1130 (p.Ser1130Argfs*29). Ascertainment of 14 additional cats from founder lineages from Canada, France and different areas of the USA identified four additional loss of function HR variants likely causing the highly similar phenotypic hair coat across the diverse cats. The novel variants in HR for cat hypotrichia can now be established between minor differences in the phenotypic presentations., Competing Interests: Ethical approval: All procedures performed in studies involving animals were in accordance with the ethical standards of the University of Missouri institutional animal care and use protocol 8701 and 8313.

Purpose: The goal of this data challenge was to create a structured dynamic with the following objectives: (1) teach radiologists the new rules of General Data Protection Regulation (GDPR), while building a large multicentric prospective database of ultrasound, computed tomography (CT) and MRI patient images; (2) build a network including radiologists, researchers, start-ups, large companies, and students from engineering schools, and; (3) provide all French stakeholders working together during 5 data challenges with a secured framework, offering a realistic picture of the benefits and concerns in October 2018., Materials and Methods: Relevant clinical questions were chosen by the Société Francaise de Radiologie. The challenge was designed to respect all French ethical and data protection constraints. Multidisciplinary teams with at least one radiologist, one engineering student, and a company and/or research lab were gathered using different networks, and clinical databases were created accordingly., Results: Five challenges were launched: detection of meniscal tears on MRI, segmentation of renal cortex on CT, detection and characterization of liver lesions on ultrasound, detection of breast lesions on MRI, and characterization of thyroid cartilage lesions on CT. A total of 5,170 images within 4 months were provided for the challenge by 46 radiology services. Twenty-six multidisciplinary teams with 181 contestants worked for one month on the challenges. Three challenges, meniscal tears, renal cortex, and liver lesions, resulted in an accuracy>90%. The fourth challenge (breast) reached 82% and the lastone (thyroid) 70%., Conclusion: Theses five challenges were able to gather a large community of radiologists, engineers, researchers, and companies in a very short period of time. The accurate results of three of the five modalities suggest that artificial intelligence is a promising tool in these radiology modalities., (Copyright © 2019 Soci showét showé françaises de radiologie. Published by Elsevier Masson SAS. All rights reserved.)

Objective: To document the clinical appearance and prevalence of cataracts in a French population of Bengal cats., Methods: Two distinct populations of Bengal cats were examined as follows: (i) 51 animals recruited for evaluation of national prevalence of ocular diseases in an observational study conducted between October 2014 and November 2016 at the Alfort ophthalmology unit; (ii) 12 patients referred for cataract diagnosis examined at a veterinary eye clinic located in central France, between December 2014 and February 2016. Buccal swabs or blood samples for DNA analysis were collected from all patients. The pedigrees of the examined Bengal cats were also investigated., Results: Cataracts were diagnosed in 23 of 51 (45%) cats in the observational study and in all cats in the referral population, mostly bilaterally. Visual impairment was never reported. Age of subjects affected by cataracts ranged from 3 months to 9.6 years (median: 1.9 years). Cataracts were classified as nuclear cataracts (14 of 23 in the observational group and 12 of 12 in the referral group) with a focal, perinuclear, posterior, or complete nuclear pattern, or posterior polar subcapsular cataracts (10 of 23 only in the observational group). An inherited congenital origin appears to be the most likely hypothesis. The pedigree analysis suggests a hereditary component of cataract formation, but further analyses in a larger population or test matings are needed to determine the exact mode of inheritance., Conclusion: Presumed inherited cataracts appear to have a high prevalence in Bengal cats in France. The main manifestations are nuclear or subcapsular form, mostly bilateral, symmetrical, and apparently nonprogressive., (© 2017 American College of Veterinary Ophthalmologists.)