ABHD5 frameshift deletion in Golden Retrievers with ichthyosis

Abstract Ichthyoses are hereditary skin disorders characterized by the formation of scales and defects in the outermost layer of the epidermis. In dogs, at least six different breed-specific ichthyoses including a relatively common PNPLA1-related autosomal recessive ichthyosis in Golden Retrievers are known. In this study, we investigated 14 Golden Retrievers with scales that were not homozygous for the mutant PNPLA1 allele suggesting a genetically distinct new form of ichthyosis. Histopathological examinations showed lamellar, orthokeratotic hyperkeratosis and mildly hyperplastic epidermis that led to the diagnosis of a non-epidermolytic ichthyosis. Combined linkage and homozygosity mapping in 14 cases and 30 non-affected family members delimited a critical interval of ∼12.7 Mb on chromosome 23. Whole-genome sequencing of an affected dog revealed a single protein-changing variant within this region that was not present in 795 control genomes. The identified variant is a 14 bp deletion in the ABHD5 gene (c.1006_1019del), leading to a frameshift and altering the last 14 codons p.(Asp336Serfs*6). The genotypes at this variant showed perfect co-segregation with the ichthyosis phenotype in a large family comprising 14 cases and 72 controls. ABHD5 encodes an acyltransferase required for lipid metabolism. In humans, variants in ABHD5 cause Chanarin-Dorfman syndrome, a neutral lipid storage disease with ichthyosis. Our data in dogs together with the knowledge on the effects of ABHD5 variants in humans strongly suggest ABHD5:c.1006_1019del as candidate causative genetic variant for a new canine form of ichthyosis, which we propose to designate as Golden Retriever ichthyosis type 2 (ICH2).

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PRKG2 Splice Site Variant in Dogo Argentino Dogs with Disproportionate Dwarfism

Genes ◽

10.3390/genes12101489 ◽

2021 ◽

Vol 12 (10) ◽

pp. 1489

Author(s):

Gabriela Rudd Garces ◽

Maria Elena Turba ◽

Myriam Muracchini ◽

Alessia Diana ◽

Vidhya Jagannathan ◽

...

Keyword(s):

Autosomal Recessive ◽

Donor Site ◽

Genetic Defect ◽

Autosomal Recessive Inheritance ◽

Homozygosity Mapping ◽

Splice Donor Site ◽

Loss Of Function ◽

Gene Encoding ◽

Encoding Protein

Dwarfism phenotypes occur in many species and may be caused by genetic or environmental factors. In this study, we investigated a family of nine Dogo Argentino dogs, in which two dogs were affected by disproportionate dwarfism. Radiographs of an affected dog revealed a decreased level of endochondral ossification in its growth plates, and a premature closure of the distal ulnar physes. The pedigree of the dogs presented evidence of monogenic autosomal recessive inheritance; combined linkage and homozygosity mapping assigned the most likely position of a potential genetic defect to 34 genome segments, totaling 125 Mb. The genome of an affected dog was sequenced and compared to 795 control genomes. The prioritization of private variants revealed a clear top candidate variant for the observed dwarfism. This variant, PRKG2:XM_022413533.1:c.1634 + 1G>T, affects the splice donor site and is therefore predicted to disrupt the function of the PKRG2 gene encoding protein, kinase cGMP-dependent type 2, a known regulator of chondrocyte differentiation. The genotypes of the PRKG2 variant were perfectly associated with the phenotype in the studied family of dogs. PRKG2 loss-of-function variants were previously reported to cause disproportionate dwarfism in humans, cattle, mice, and rats. Together with the comparative data from other species, our data strongly suggest PRKG2:c.1634+1G>T to be a candidate causative variant for the observed dwarfism phenotype in Dogo Argentino dogs.

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Neutral Lipid Storage Diseases as Cellular Model to Study Lipid Droplet Function

Cells ◽

10.3390/cells8020187 ◽

2019 ◽

Vol 8 (2) ◽

pp. 187 ◽

Cited By ~ 19

Author(s):

Sara Missaglia ◽

Rosalind Coleman ◽

Alvaro Mordente ◽

Daniela Tavian

Keyword(s):

Neutral Lipid ◽

Autosomal Recessive ◽

Energy Homeostasis ◽

Lipid Storage ◽

Sterol Esters ◽

Lipid Storage Disease ◽

Autosomal Recessive Disorders ◽

Neutral Lipid Storage Disease ◽

Functional Knowledge ◽

Recessive Disorders

Neutral lipid storage disease with myopathy (NLSDM) and with ichthyosis (NLSDI) are rare autosomal recessive disorders caused by mutations in the PNPLA2 and in the ABHD5/CGI58 genes, respectively. These genes encode the adipose triglyceride lipase (ATGL) and α-β hydrolase domain 5 (ABHD5) proteins, which play key roles in the function of lipid droplets (LDs). LDs, the main cellular storage sites of triacylglycerols and sterol esters, are highly dynamic organelles. Indeed, LDs are critical for both lipid metabolism and energy homeostasis. Partial or total PNPLA2 or ABHD5/CGI58 knockdown is characteristic of the cells of NLSD patients; thus, these cells are natural models with which one can unravel LD function. In this review we firstly summarize genetic and clinical data collected from NLSD patients, focusing particularly on muscle, skin, heart, and liver damage due to impaired LD function. Then, we discuss how NLSD cells were used to investigate and expand the current structural and functional knowledge of LDs.

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Maternal Isodisomy of Chromosome 3 Combined with a De Novo Mutation in the ABHD5 Gene Causes Autosomal Recessive Chanarin-Dorfman Syndrome

Genes ◽

10.3390/genes12081164 ◽

2021 ◽

Vol 12 (8) ◽

pp. 1164

Author(s):

Julia Kopp ◽

Cristina Has ◽

Alrun Hotz ◽

Sarah C. Grünert ◽

Judith Fischer

Keyword(s):

Autosomal Recessive ◽

De Novo ◽

Uniparental Disomy ◽

Rare Event ◽

De Novo Mutation ◽

Chromosome 3 ◽

Lipid Storage Disease ◽

First Case ◽

Neutral Lipid Storage Disease ◽

Biallelic Mutations

Autosomal recessive Chanarin-Dorfman syndrome (CDS, MIM #275630) is defined as a neutral lipid storage disease with ichthyosis (NLSDI) due to an accumulation of lipid droplets in a variety of different tissues including liver and muscle cells, leucocytes, fibroblasts and nerve cells It is caused by biallelic mutations in the abhydrolase domain containing 5 gene (ABHD5, MIM *604780) which is localized on the short arm of chromosome 3. Here we report an 18 month-old girl in whom we have identified the homozygous ABHD5 mutation c.700C > T, p.(Arg234*). Since none of the parents carried this point mutation, parentage was confirmed by microsatellite marker analysis. Suspected uniparental disomy (UPD) was confirmed by microsatellite genotyping over the entire chromosome 3 and indicated a maternal origin. UPD is an extremely rare event that is not necessarily pathogenic, but may cause disease if the affected chromosome contains genes that are imprinted. Here we report the first case of Chanarin-Dorfman syndrome due to a de novo ABHD5 mutation in the maternal germ cell, combined with a maternal uniparental isodisomy of chromosome 3. This case demonstrates that genetic analysis of the patient and both parents is crucial to provide correct genetic counseling.

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INTS13 Mutations Causing a Developmental Ciliopathy Disrupt Integrator Complex Assembly

10.1101/2020.07.20.209130 ◽

2020 ◽

Author(s):

Lauren G. Mascibroda ◽

Mohammad Shboul ◽

Nathan D. Elrod ◽

Laurence Colleaux ◽

Hanan Hamamy ◽

...

Keyword(s):

Autosomal Recessive ◽

Cultured Cells ◽

Germline Mutations ◽

Homozygosity Mapping ◽

Congenital Disorders ◽

C Terminus ◽

The Face ◽

A Subunit ◽

Discrete Domain

ABSTRACTOral-facial-digital syndromes (OFD) are a heterogeneous group of congenital disorders characterized by malformations of the face and oral cavity, and digit anomalies. To date, mutations in 12 ciliary-related genes have been identified that cause several types of OFD, suggesting that OFDs constitute a subgroup of developmental ciliopathies. Through homozygosity mapping and exome sequencing of two families with variable OFD type 2, we identified distinct germline mutations in INTS13, a subunit of the Integrator complex. This 14-component complex associates with RNAPII and can cleave nascent RNA to modulate gene expression. We determined that INTS13 utilizes a discrete domain within its C-terminus to bind the Integrator cleavage module, which is disrupted by the identified germline INTS13 mutations. Depletion of INTS13 disrupts ciliogenesis in human cultured cells and causes dysregulation of a broad collection of ciliary genes. Accordingly, its knockdown in Xenopus embryos lead to motile cilia anomalies. Altogether, we show that mutations in INTS13 cause an autosomal recessive ciliopathy, which reveals key interactions within Integrator components.

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Ataxia with oculomotor apraxia type 2: an evolving axonal neuropathy

Practical Neurology ◽

10.1136/practneurol-2017-001711 ◽

2017 ◽

Vol 18 (1) ◽

pp. 52-56

Author(s):

Tahira N Choudry ◽

David Hilton-Jones ◽

Graham Lennox ◽

Henry Houlden

Keyword(s):

Autosomal Recessive ◽

Age Of Onset ◽

Axonal Neuropathy ◽

Elevated Serum ◽

Cerebellar Atrophy ◽

Recessive Ataxia ◽

Autosomal Recessive Ataxia ◽

Oculomotor Apraxia ◽

Ataxia With Oculomotor Apraxia

A 23-year-old woman had presented initially to a podiatrist complaining of poorly fitting shoes during her adolescence. After extensive neurological review, she was diagnosed with ataxia with oculomotor apraxia type 2. This is a progressive autosomal recessive ataxia associated with cerebellar atrophy, peripheral neuropathy and an elevated serum α-fetoprotein. Within Europe, it is the most frequent autosomal recessive ataxia after Friedreich’s ataxia and is due to mutations in the senataxin (SETX) gene. The age of onset is approximately 15 years.The diagnosis of oculomotor apraxia type 2 is often challenging. We provide a framework for assessing a young ataxic patient with or without oculomotor apraxia and review clues that will aid diagnosis. The prognosis, level of disability, cancer and immunosuppression risk all markedly differ between the conditions. Patients and their families need the correct diagnosis for genetic counselling, management and long-term surveillance with appropriate subspecialty services.

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The Lack of the C-Terminal Domain of Adipose Triglyceride Lipase Causes Neutral Lipid Storage Disease through Impaired Interactions with Lipid Droplets

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2007-2247 ◽

2008 ◽

Vol 93 (7) ◽

pp. 2877-2884 ◽

Cited By ~ 73

Author(s):

Kunihisa Kobayashi ◽

Toyoshi Inoguchi ◽

Yasutaka Maeda ◽

Naoki Nakashima ◽

Asako Kuwano ◽

...

Keyword(s):

Neutral Lipid ◽

Lipid Droplets ◽

Storage Disease ◽

Lipid Storage ◽

Adipose Triglyceride Lipase ◽

Lipid Storage Disease ◽

Triglyceride Lipase ◽

Terminal Domain ◽

Neutral Lipid Storage Disease

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Autosomal recessive cutis laxa type 2

10.32388/u0faur ◽

2020 ◽

Author(s):

Keyword(s):

Autosomal Recessive ◽

Cutis Laxa

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Gaucher's Disease - A case report

MVP Journal of Medical Sciences ◽

10.18311/mvpjms/2015/v2/i2/788 ◽

2015 ◽

Vol 2 (2) ◽

pp. 130

Author(s):

Preeti Bajaj ◽

Jyoti Kasture ◽

Balbir Singh Shah

Keyword(s):

Autosomal Recessive ◽

Genetic Disorder ◽

Early Adulthood ◽

Lysosomal Storage ◽

Gaucher's Disease ◽

Gaucher’S Disease ◽

Type 3 ◽

Storage Disorders

Gaucher's Disease (GD) is an autosomal recessive systemic lysosomal storage disorder which is characterized by glucocerebroside deposition in cells of the macrophage-monocyte system as a result of a deficiency in lysosomal P-glycosidase (glucocerebrosidase). GD is a rare genetic disorder. It is the most common amongst the lysosomal storage disorders. GD has been categorised into three types based on the presence of central nervous involvement1. Type 1 is a non-neuronopathic form that presents in childhood or early adulthood. Type 2 is acute neuronopathic form that presents in childhood. It progresses rapidly and is fatal. Type 3 is chronic non-neuronopathic form that presents in childhood but is slowly progressive. Here we describe a case of a three and a half year old male child in whom a diagnosis of Gaucher's disease was made based on bone marrow biopsy and later confirmed by glucocerebrosidase levels estimation.

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