A Missense Variant in SLC39A4 in a Litter of Turkish Van Cats with Acrodermatitis Enteropathica

In a litter of Turkish Van cats, three out of six kittens developed severe signs of skin disease, diarrhea, and systemic signs of stunted growth at 6 weeks of age. Massive secondary infections of the skin lesions evolved. Histopathological examinations showed a mild to moderate hyperplastic epidermis, covered by a thick layer of laminar to compact, mostly parakeratotic keratin. The dermis was infiltrated with moderate amounts of lymphocytes and plasma cells. Due to the severity of the clinical signs, one affected kitten died and the other two had to be euthanized. We sequenced the genome of one affected kitten and compared the data to 54 control genomes. A search for private variants in the two candidate genes for the observed phenotype, MKLN1 and SLC39A4, revealed a single protein-changing variant, SLC39A4:c.1057G>C or p.Gly353Arg. The solute carrier family 39 member 4 gene (SLC39A4) encodes an intestinal zinc transporter required for the uptake of dietary zinc. The variant is predicted to change a highly conserved glycine residue within the first transmembrane domain, which most likely leads to a loss of function. The genotypes of the index family showed the expected co-segregation with the phenotype and the mutant allele was absent from 173 unrelated control cats. Together with the knowledge on the effects of SLC39A4 variants in other species, these data suggest SLC39A4:c.1057G>C as candidate causative genetic variant for the phenotype in the investigated kittens. In line with the human phenotype, we propose to designate this disease acrodermatitis enteropathica (AE).

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Structural defects caused by Acrodermatitis Enteropathica mutations in the extracellular domain account for mistrafficking and malfunction of ZIP4

10.1101/2020.08.16.253294 ◽

2020 ◽

Author(s):

Eziz Kuliyev ◽

Chi Zhang ◽

Dexin Sui ◽

Jian Hu

Keyword(s):

Transmembrane Domain ◽

Extracellular Domain ◽

Zinc Uptake ◽

Structural Defects ◽

Acrodermatitis Enteropathica ◽

Missense Mutations ◽

Zinc Transport ◽

Loss Of Function ◽

Transporter Family ◽

Zip Family

AbstractZIP4 is a representative member of the Zrt-/Irt-like protein (ZIP) transporter family and responsible for zinc uptake from diet. Loss-of-function mutations of human ZIP4 (hZIP4) drastically reduce zinc absorption, causing a life-threatening autosomal recessive disorder, Acrodermatitis Enteropathica (AE). Although the zinc transport machinery is located in the transmembrane domain conserved in the entire ZIP family, half of the missense mutations occur in the extracellular domain (ECD) of hZIP4, which is only present in a fraction of mammalian ZIPs. How the AE-causing mutations in the ECD lead to ZIP4 malfunction has not be fully clarified. In this work, we characterized all the seven confirmed AE-causing missense mutations in hZIP4-ECD and found that the variants exhibited completely abolished zinc transport activity measured in a cell-based transport assay. Although the variants were able to be expressed in HEK293T cells, they failed to traffic to cell surface and were largely retained in the ER with immature glycosylation. When the corresponding mutations were introduced in the ECD of ZIP4 from Pteropus Alecto, a close homolog of hZIP4, the variants exhibited impaired protein folding and reduced thermal stability, which likely account for intracellular mistrafficking of the AE-associated variants and as such a total loss of zinc uptake in cells. This work provides a molecular pathogenic mechanism for AE, which lays out a basis for potential therapy using small molecular chaperones.

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LAMB3 Missense Variant in Australian Shepherd Dogs with Junctional Epidermolysis Bullosa

Genes ◽

10.3390/genes11091055 ◽

2020 ◽

Vol 11 (9) ◽

pp. 1055 ◽

Cited By ~ 1

Author(s):

Sarah Kiener ◽

Aurore Laprais ◽

Elizabeth A. Mauldin ◽

Vidhya Jagannathan ◽

Thierry Olivry ◽

...

Keyword(s):

Basement Membrane ◽

Epidermolysis Bullosa ◽

Clinical Signs ◽

Autosomal Recessive Inheritance ◽

Missense Variant ◽

Loss Of Function ◽

Junctional Epidermolysis Bullosa ◽

Skin Fragility ◽

Close Relatives ◽

Tentative Diagnosis

In a highly inbred Australian Shepherd litter, three of the five puppies developed widespread ulcers of the skin, footpads, and oral mucosa within the first weeks of life. Histopathological examinations demonstrated clefting of the epidermis from the underlying dermis within or just below the basement membrane, which led to a tentative diagnosis of junctional epidermolysis bullosa (JEB) with autosomal recessive inheritance. Endoscopy in one affected dog also demonstrated separation between the epithelium and underlying tissue in the gastrointestinal tract. As a result of the severity of the clinical signs, all three dogs had to be euthanized. We sequenced the genome of one affected puppy and compared the data to 73 control genomes. A search for private variants in 37 known candidate genes for skin fragility phenotypes revealed a single protein-changing variant, LAMB3:c.1174T>C, or p.Cys392Arg. The variant was predicted to change a conserved cysteine in the laminin β3 subunit of the heterotrimeric laminin-322, which mediates the binding of the epidermal basement membrane to the underlying dermis. Loss-of-function variants in the human LAMB3 gene lead to recessive forms of JEB. We confirmed the expected co-segregation of the genotypes in the Australian Shepherd family. The mutant allele was homozygous in two genotyped cases and heterozygous in three non-affected close relatives. It was not found in 242 other controls from the Australian Shepherd breed, nor in more than 600 other controls. These data suggest that LAMB3:c.1174T>C represents the causative variant. To the best of our knowledge, this study represents the first report of a LAMB3-related JEB in domestic animals.

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Spontaneous and experimental poisoning by Froelichia humboldtiana in cattle

Pesquisa Veterinária Brasileira ◽

10.1590/1678-5150-pvb-6351 ◽

2020 ◽

Vol 40 (1) ◽

pp. 1-6

Author(s):

Givaldo B. Silva Filho ◽

Hisadora A.S. Chaves ◽

Raquel F. Albuquerque ◽

Paulo E. Souza ◽

Maria E.Q. Vieira ◽

...

Keyword(s):

Plasma Cells ◽

Clinical Signs ◽

Serum Levels ◽

Skin Lesions ◽

Northeastern Brazil ◽

Indirect Bilirubin ◽

The Third ◽

Experimental Group ◽

Average Consumption ◽

Epidermal Necrosis

ABSTRACT: The aim of this work was to describe the epidemiological, clinical and pathological aspects of two outbreaks of spontaneous poisoning caused by Froelichia humboldtiana in cattle in Pernambuco, northeastern Brazil and reproduce experimentally this poisoning in cattle. Spontaneous poisonings of primary photosensitization occurred in two farms at the municipalities of Cachoeirinha and São Caetano and affected twenty-two adult bovines and two suckling calves after the rainy season. All bovines have recovered 21 days after they were removed from the pasture. To reproduce experimental poisoning, three cows and a calf were maintained in a pasture with 1ha composed by F. humboldtiana during 14 days. Clinical signs and skin lesions were similar in both spontaneous and experimental poisoning and consisted of cutaneous itching and hyperemia of non-pigmented areas of skin that evolved into edema, exudative dermatitis and extensive areas of skin necrosis. Serum levels of aspartate aminotransferase (AST), gamma glutamyltransferase (GGT), total, direct and indirect bilirubin were normal in all cattle examined. Histologically, lesions consisted of epidermal necrosis, hyperkeratosis with large amounts of degenerate neutrophils and acanthosis. In the dermis, edema and inflammatory infiltrate composed of eosinophils, lymphocytes and plasma cells mainly around the blood vessels were observed. In the experimental group, clinical signs of photosensitization were observed after the third day of F. humboldtiana consumption. The suckling calf displayed mild clinical signs of photodermatitis on the 8th day of the experiment. It was estimated that the average consumption of F. humboldtiana necessary to initiate clinical signs in each adult bovine was 78kg.

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Multisystemic eosinophilic epitheliotropic disease in a horse in Brazil

Ciência Rural ◽

10.1590/0103-8478cr20160896 ◽

2017 ◽

Vol 47 (5) ◽

Author(s):

Cláudio João Mourão Laisse ◽

Lismara Castro do Nascimento ◽

Welden Panziera ◽

Elizabeth Caldas Soares ◽

Denise Bicca Fernandes ◽

...

Keyword(s):

Plasma Cells ◽

Clinical Signs ◽

Giant Cells ◽

Skin Lesions ◽

Substantial Improvement ◽

Mesenteric Lymph Nodes ◽

Tissue Proliferation ◽

Mesenteric Lymph ◽

Progressive Weight Loss ◽

Gastric Reflux

ABSTRACT: Equine multisystemic eosinophilic epitheliotropic disease (MEED) is a rare disease, characterized by eosinophilia and eosinophilic infiltration of several organs. A 5-year-old horse presented pruritus, areas of alopecia, and moderate eosinophilia. The horse was treated with corticosteroids and antibiotics without substantial improvement; and after the disease progressed to fever, diarrhea, gastric reflux and progressive weight loss. Due to poor prognosis the horse was euthanized. Necropsy revealed poor body condition, multiple to coalescing foci of alopecia, with epidermal ulcerations and crusts on the head and distal parts of the limbs. The proximal duodenum was enlarged, with 3 intraluminal nodules. Histopathological evaluation revealed eosinophilic granulomas in the skin, oral mucosa, duodenum, pancreas, and mesenteric lymph nodes, which were associated with infiltrates of eosinophils, lymphocytes, macrophages, multinucleated giant cells, and occasional plasma cells, along with fibrovascular connective tissue proliferation. MEED should be included in the differential diagnosis of horses with skin lesions concomitant with clinical signs of gastrointestinal illness.

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Novel CARMIL2 loss-of-function variants are associated with pediatric inflammatory bowel disease

Scientific Reports ◽

10.1038/s41598-021-85399-9 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Luca Bosa ◽

Vritika Batura ◽

Davide Colavito ◽

Karoline Fiedler ◽

Paola Gaio ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

Bowel Disease ◽

Early Onset ◽

Clinical Signs ◽

Missense Variant ◽

Loss Of Function ◽

Altered Expression ◽

Autoimmune Polyendocrine Syndrome ◽

Altered Expression Pattern ◽

Inflammatory Bowel

AbstractCARMIL2 is required for CD28-mediated co-stimulation of NF-κB signaling in T cells and its deficiency has been associated with primary immunodeficiency and, recently, very early onset inflammatory bowel disease (IBD). Here we describe the identification of novel biallelic CARMIL2 variants in three patients presenting with pediatric-onset IBD and in one with autoimmune polyendocrine syndrome (APS). None manifested overt clinical signs of immunodeficiency before their diagnosis. The first patient presented with very early onset IBD. His brother was found homozygous for the same CARMIL2 null variant and diagnosed with APS. Two other IBD patients were found homozygous for a nonsense and a missense CARMIL2 variant, respectively, and they both experienced a complicated postoperative course marked by severe infections. Immunostaining of bowel biopsies showed reduced CARMIL2 expression in all the three patients with IBD. Western blot and immunofluorescence of transfected cells revealed an altered expression pattern of the missense variant. Our work expands the genotypic and phenotypic spectrum of CARMIL2 deficiency, which can present with either IBD or APS, aside from classic immunodeficiency manifestations. CARMIL2 should be included in the diagnostic work-up of patients with suspected monogenic IBD.

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L2HGDH Missense Variant in a Cat with L-2-Hydroxyglutaric Aciduria

Genes ◽

10.3390/genes12050682 ◽

2021 ◽

Vol 12 (5) ◽

pp. 682

Author(s):

Matthias Christen ◽

Nils Janzen ◽

Anne Fraser ◽

Adrian C. Sewell ◽

Vidhya Jagannathan ◽

...

Keyword(s):

Current Knowledge ◽

Genetic Defect ◽

Clinical Signs ◽

Missense Variant ◽

Microcytic Anemia ◽

Abnormal Behavior ◽

Functional Candidate Gene ◽

History Of ◽

The Brain ◽

Hydroxyglutaric Acid

A 7-month-old, spayed female, domestic longhair cat with L-2-hydroxyglutaric aciduria (L-2-HGA) was investigated. The aim of this study was to investigate the clinical signs, metabolic changes and underlying genetic defect. The owner of the cat reported a 4-month history of multiple paroxysmal seizure-like episodes, characterized by running around the house, often in circles, with abnormal behavior, bumping into obstacles, salivating and often urinating. The episodes were followed by a period of disorientation and inappetence. Neurological examination revealed an absent bilateral menace response. Routine blood work revealed mild microcytic anemia but biochemistry, ammonia, lactate and pre- and post-prandial bile acids were unremarkable. MRI of the brain identified multifocal, bilaterally symmetrical and T2-weighted hyperintensities within the prosencephalon, mesencephalon and metencephalon, primarily affecting the grey matter. Urinary organic acids identified highly increased levels of L-2-hydroxyglutaric acid. The cat was treated with the anticonvulsants levetiracetam and phenobarbitone and has been seizure-free for 16 months. We sequenced the genome of the affected cat and compared the data to 48 control genomes. L2HGDH, coding for L-2-hydroxyglutarate dehydrogenase, was investigated as the top functional candidate gene. This search revealed a single private protein-changing variant in the affected cat. The identified homozygous variant, XM_023255678.1:c.1301A>G, is predicted to result in an amino acid change in the L2HGDH protein, XP_023111446.1:p.His434Arg. The available clinical and biochemical data together with current knowledge about L2HGDH variants and their functional impact in humans and dogs allow us to classify the p.His434Arg variant as a causative variant for the observed neurological signs in this cat.

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GWAS of serum ALT and AST reveals an association of SLC30A10 Thr95Ile with hypermanganesemia symptoms

Nature Communications ◽

10.1038/s41467-021-24563-1 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Lucas D. Ward ◽

Ho-Chou Tu ◽

Chelsea B. Quenneville ◽

Shira Tsour ◽

Alexander O. Flynn-Carroll ◽

...

Keyword(s):

Bile Duct ◽

Extrahepatic Bile Duct ◽

Association Studies ◽

Missense Variant ◽

Deficiency Anemia ◽

Genome Wide Association Studies ◽

Loss Of Function ◽

Extrahepatic Bile Duct Cancer ◽

Hepatocellular Damage ◽

Increased Risk

AbstractUnderstanding mechanisms of hepatocellular damage may lead to new treatments for liver disease, and genome-wide association studies (GWAS) of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) serum activities have proven useful for investigating liver biology. Here we report 100 loci associating with both enzymes, using GWAS across 411,048 subjects in the UK Biobank. The rare missense variant SLC30A10 Thr95Ile (rs188273166) associates with the largest elevation of both enzymes, and this association replicates in the DiscovEHR study. SLC30A10 excretes manganese from the liver to the bile duct, and rare homozygous loss of function causes the syndrome hypermanganesemia with dystonia-1 (HMNDYT1) which involves cirrhosis. Consistent with hematological symptoms of hypermanganesemia, SLC30A10 Thr95Ile carriers have increased hematocrit and risk of iron deficiency anemia. Carriers also have increased risk of extrahepatic bile duct cancer. These results suggest that genetic variation in SLC30A10 adversely affects more individuals than patients with diagnosed HMNDYT1.

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Emerging Role of ODC1 in Neurodevelopmental Disorders and Brain Development

Genes ◽

10.3390/genes12040470 ◽

2021 ◽

Vol 12 (4) ◽

pp. 470

Author(s):

Jeremy W. Prokop ◽

Caleb P. Bupp ◽

Austin Frisch ◽

Stephanie M. Bilinovich ◽

Daniel B. Campbell ◽

...

Keyword(s):

Brain Development ◽

Neural Progenitor Cells ◽

Neurodevelopmental Disorder ◽

Fetal Brain ◽

Missense Variant ◽

Neural Progenitor ◽

Loss Of Function ◽

Gain Of Function ◽

Systematic Analysis ◽

Function Expression

Ornithine decarboxylase 1 (ODC1 gene) has been linked through gain-of-function variants to a rare disease featuring developmental delay, alopecia, macrocephaly, and structural brain anomalies. ODC1 has been linked to additional diseases like cancer, with growing evidence for neurological contributions to schizophrenia, mood disorders, anxiety, epilepsy, learning, and suicidal behavior. The evidence of ODC1 connection to neural disorders highlights the need for a systematic analysis of ODC1 genotype-to-phenotype associations. An analysis of variants from ClinVar, Geno2MP, TOPMed, gnomAD, and COSMIC revealed an intellectual disability and seizure connected loss-of-function variant, ODC G84R (rs138359527, NC_000002.12:g.10444500C > T). The missense variant is found in ~1% of South Asian individuals and results in 2.5-fold decrease in enzyme function. Expression quantitative trait loci (eQTLs) reveal multiple functionally annotated, non-coding variants regulating ODC1 that associate with psychiatric/neurological phenotypes. Further dissection of RNA-Seq during fetal brain development and within cerebral organoids showed an association of ODC1 expression with cell proliferation of neural progenitor cells, suggesting gain-of-function variants with neural over-proliferation and loss-of-function variants with neural depletion. The linkage from the expression data of ODC1 in early neural progenitor proliferation to phenotypes of neurodevelopmental delay and to the connection of polyamine metabolites in brain function establish ODC1 as a bona fide neurodevelopmental disorder gene.

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A novel de novo DDX3X missense variant in a female with brachycephaly and intellectual disability: a case report

Italian Journal of Pediatrics ◽

10.1186/s13052-021-01033-4 ◽

2021 ◽

Vol 47 (1) ◽

Author(s):

Giada Moresco ◽

Jole Costanza ◽

Carlo Santaniello ◽

Ornella Rondinone ◽

Federico Grilli ◽

...

Keyword(s):

Intellectual Disability ◽

Clinical Presentation ◽

De Novo ◽

Clinical Signs ◽

Missense Variant ◽

Psychomotor Development ◽

Helicase Domain ◽

Protein Activity ◽

Mrna Metabolism ◽

Pathogenic Variants

Abstract Background De novo pathogenic variants in the DDX3X gene are reported to account for 1–3% of unexplained intellectual disability (ID) in females, leading to the rare disease known as DDX3X syndrome (MRXSSB, OMIM #300958). Besides ID, these patients manifest a variable clinical presentation, which includes neurological and behavioral defects, and abnormal brain MRIs. Case presentation We report a 10-year-old girl affected by delayed psychomotor development, delayed myelination, and polymicrogyria (PMG). We identified a novel de novo missense mutation in the DDX3X gene (c.625C > G) by whole exome sequencing (WES). The DDX3X gene encodes a DEAD-box ATP-dependent RNA-helicase broadly implicated in gene expression through regulation of mRNA metabolism. The identified mutation is located just upstream the helicase domain and is suggested to impair the protein activity, thus resulting in the altered translation of DDX3X-dependent mRNAs. The proband, presenting with the typical PMG phenotype related to the syndrome, does not show other clinical signs frequently reported in presence of missense DDX3X mutations that are associated with a most severe clinical presentation. In addition, she has brachycephaly, never described in female DDX3X patients, and macroglossia, that has never been associated with the syndrome. Conclusions This case expands the knowledge of DDX3X pathogenic variants and the associated DDX3X syndrome phenotypic spectrum.

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Variable Expressivity of the Beckwith-Wiedemann Syndrome in Four Pedigrees Segregating Loss-of-Function Variants of CDKN1C

Genes ◽

10.3390/genes12050706 ◽

2021 ◽

Vol 12 (5) ◽

pp. 706

Author(s):

Angela Sparago ◽

Flavia Cerrato ◽

Laura Pignata ◽

Francisco Cammarata-Scalisi ◽

Livia Garavelli ◽

...

Keyword(s):

Cellular Proliferation ◽

Missense Variant ◽

Abdominal Wall Defects ◽

Loss Of Function ◽

Nonsense Mutations ◽

Molecular Defects ◽

Variable Expressivity ◽

Imprinting Disorder ◽

Perinatal Lethality ◽

Intrafamilial Variability

Beckwith-Wiedemann syndrome (BWS) is an imprinting disorder characterized by prenatal and/or postnatal overgrowth, organomegaly, abdominal wall defects and tumor predisposition. CDKN1C is a maternally expressed gene of the 11p15.5 chromosomal region and is regulated by the imprinting control region IC2. It negatively controls cellular proliferation, and its expression or activity are frequently reduced in BWS. In particular, loss of IC2 methylation is associated with CDKN1C silencing in the majority of sporadic BWS cases, and maternally inherited loss-of-function variants of CDKN1C are the most frequent molecular defects of familial BWS. We have identified, using Sanger sequencing, novel CDKN1C variants in three families with recurrent cases of BWS, and a previously reported variant in a woman with recurrent miscarriages with exomphalos. Clinical evaluation of the patients showed variable manifestation of the disease. The frameshift and nonsense variants were consistently associated with exomphalos, while the missense variant caused a less severe phenotype. Pregnancy loss and perinatal lethality were found in the families segregating nonsense mutations. Intrafamilial variability of the clinical BWS features was observed, even between siblings. Our data are indicative of severe BWS phenotypes that, with variable expressivity, may be associated with both frameshift and nonsense variants of CDKN1C.

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