scholarly journals LAMB3 Missense Variant in Australian Shepherd Dogs with Junctional Epidermolysis Bullosa

Genes ◽  
2020 ◽  
Vol 11 (9) ◽  
pp. 1055 ◽  
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.

scholarly journals A Novel Phenotype of Junctional Epidermolysis Bullosa with Transient Skin Fragility and Predominant Ocular Involvement Responsive to Human Amniotic Membrane Eyedrops

Genes ◽  
2021 ◽  
Vol 12 (5) ◽  
pp. 716
Author(s):  
Daniele Castiglia ◽  
Paola Fortugno ◽  
Angelo Giuseppe Condorelli ◽  
Sabina Barresi ◽  
Naomi De Luca ◽  
...  
Keyword(s):  
Amniotic Membrane ◽  
Epidermolysis Bullosa ◽  
Ocular Involvement ◽  
Human Amniotic Membrane ◽  
Vitro Assay ◽  
Junctional Epidermolysis Bullosa ◽  
Mucosal Involvement ◽  
Skin Fragility ◽  
Laminin 332

Junctional epidermolysis bullosa (JEB) is a clinically and genetically heterogeneous skin fragility disorder frequently caused by mutations in genes encoding the epithelial laminin isoform, laminin-332. JEB patients also present mucosal involvement, including painful corneal lesions. Recurrent corneal abrasions may lead to corneal opacities and visual impairment. Current treatments are merely supportive. We report a novel JEB phenotype distinguished by the complete resolution of skin fragility in infancy and persistent ocular involvement with unremitting and painful corneal abrasions. Biallelic LAMB3 mutations c.3052-5C>G and c.3492_3493delCG were identified as the molecular basis for this phenotype, with one mutation being a hypomorphic splice variant that allows residual wild-type laminin-332 production. The reduced laminin-332 level was associated with impaired keratinocyte adhesion. Then, we also investigated the therapeutic power of a human amniotic membrane (AM) eyedrop preparation for corneal lesions. AM were isolated from placenta donors, according to a procedure preserving the AM biological characteristics as a tissue, and confirmed to contain laminin-332. We found that AM eyedrop preparation could restore keratinocyte adhesion in an in vitro assay. Of note, AM eyedrop administration to the patient resulted in long-lasting remission of her ocular manifestations. Our findings suggest that AM eyedrops could represent an effective, non-invasive, simple-to-handle treatment for corneal lesions in patients with JEB and possibly other EB forms.

scholarly journals Phenotype and Variant Spectrum in the LAMB3 Form of Amelogenesis Imperfecta

2019 ◽  
Vol 98 (6) ◽  
pp. 698-704 ◽  
Author(s):  
C.E.L. Smith ◽  
J.A. Poulter ◽  
S.J. Brookes ◽  
G. Murillo ◽  
S. Silva ◽  
...  
Keyword(s):  
Epidermolysis Bullosa ◽  
Third Molar ◽  
Dental Enamel ◽  
Amelogenesis Imperfecta ◽  
Splice Acceptor Site ◽  
Acceptor Site ◽  
Loss Of Function ◽  
Inherited Disorders ◽  
Junctional Epidermolysis Bullosa ◽  
Molar Teeth

Amelogenesis imperfecta (AI) is a heterogeneous group of inherited disorders characterized by abnormal formation of dental enamel, either in isolation or as part of a syndrome. Heterozygous variants in laminin subunit beta 3 ( LAMB3) cause AI with dominant inheritance in the absence of other cosegregating clinical features. In contrast, biallelic loss-of-function variants in LAMB3 cause recessive junctional epidermolysis bullosa, characterized by life-threatening skin fragility. We identified 2 families segregating autosomal dominant AI with variable degrees of a distinctive hypoplastic phenotype due to pathogenic variants in LAMB3. Whole exome sequencing revealed a nonsense variant (c.3340G>T, p.E1114*) within the final exon in family 1, while Sanger sequencing in family 2 revealed a variant (c.3383-1G>A) in the canonical splice acceptor site of the final exon. Analysis of cDNA from family 2 revealed retention of the final intron leading to a premature termination codon. Two unerupted third molar teeth from individual IV:5 in family 2 were subject to computerized tomography and scanning electron microscopy. LAMB3 molar teeth have a multitude of cusps versus matched controls. LAMB3 enamel was well mineralized but pitted. The architecture of the initially secreted enamel was abnormal, with cervical enamel appearing much less severely affected than coronal enamel. This study further defines the variations in phenotype-genotype correlation for AI due to variants in LAMB3, underlines the clustering of nonsense and frameshift variants causing AI in the absence of junctional epidermolysis bullosa, and highlights the shared AI phenotype arising from variants in genes coding for hemidesmosome proteins.

scholarly journals Gentamicin induces LAMB3 nonsense mutation readthrough and restores functional laminin 332 in junctional epidermolysis bullosa

2018 ◽  
Vol 115 (28) ◽  
pp. E6536-E6545 ◽  
Author(s):  
Vadim Lincoln ◽  
Jon Cogan ◽  
Yingping Hou ◽  
Michaela Hirsch ◽  
Michelle Hao ◽  
...  
Keyword(s):  
Epidermolysis Bullosa ◽  
Skin Diseases ◽  
Growth Potential ◽  
Equivalent Model ◽  
Expression Vectors ◽  
Loss Of Function ◽  
Nonsense Mutations ◽  
Poor Growth ◽  
Junctional Epidermolysis Bullosa ◽  
Laminin 332

Herlitz junctional epidermolysis bullosa (H-JEB) is an incurable, devastating, and mostly fatal inherited skin disease for which there is only supportive care. H-JEB is caused by loss-of-function mutations in LAMA3, LAMB3, or LAMC2, leading to complete loss of laminin 332, the major component of anchoring filaments, which mediate epidermal-dermal adherence. LAMB3 (laminin β3) mutations account for 80% of patients with H-JEB, and ∼95% of H-JEB–associated LAMB3 mutations are nonsense mutations leading to premature termination codons (PTCs). In this study, we evaluated the ability of gentamicin to induce PTC readthrough in H-JEB laminin β3-null keratinocytes transfected with expression vectors encoding eight different LAMB3 nonsense mutations. We found that gentamicin induced PTC readthrough in all eight nonsense mutations tested. We next used lentiviral vectors to generate stably transduced H-JEB cells with the R635X and C290X nonsense mutations. Incubation of these cell lines with various concentrations of gentamicin resulted in the synthesis and secretion of full-length laminin β3 in a dose-dependent and sustained manner. Importantly, the gentamicin-induced laminin β3 led to the restoration of laminin 332 assembly, secretion, and deposition within the dermal/epidermal junction, as well as proper polarization of α6β4 integrin in basal keratinocytes, as assessed by immunoblot analysis, immunofluorescent microscopy, and an in vitro 3D skin equivalent model. Finally, newly restored laminin 332 corrected the abnormal cellular phenotype of H-JEB cells by reversing abnormal cell morphology, poor growth potential, poor cell-substratum adhesion, and hypermotility. Therefore, gentamicin may offer a therapy for H-JEB and other inherited skin diseases caused by PTC mutations.

scholarly journals Challenges of the differential diagnosis between the subtypes of the junctional epidermolysis bullosa: presentation of two clinical cases

2019 ◽  
Vol 47 (1) ◽  
pp. 83-93
Author(s):  
Yu. Yu. Kotalevskaya ◽  
N. M. Marycheva
Keyword(s):  
Differential Diagnosis ◽  
Epidermolysis Bullosa ◽  
Skin Disease ◽  
Clinical Case ◽  
Molecular Genetic ◽  
Clinical Signs ◽  
Clinical Manifestations ◽  
Junctional Epidermolysis Bullosa ◽  
Reliable Determination ◽  
Clinical Cases

Background: Epidermolysis bullosa (EB) is a rare hereditary skin disease. It is subdivided into EB simplex (EBS), junctional EB (JEB), dystrophic EB (DEB) and Kindler syndrome. JEB is diagnosed in 2 per 1,000,000 of the population. There are few descriptions of clinical JEB cases in the literature. Clinical diagnosis of JEB and its subtypes is a challenge, especially in the early age. The paper presents 2 clinical cases of JEB in patients of the West Slavonic origin. Clinical case No. 1 was a girl of Ukrainian ethnicity, with confirmed definitive diagnosis of severe generalized JEB. Molecular genetic tests identified mutations of the LAMA3 gene that had not been described previously. The patient died at the age of 24 months from acute respiratory failure. When the patient was alive, her EB type and subtype was not possible to identify, because she had a combination of clinical manifestations typical for various JEB subtypes. Despite such symptoms as hoarse voice, stenoses, granulation tissue of typical location, laryngeal granulations, the girl was steadily gaining weight, with some periods of relative stabilization of the skin disease; she also had longer life longevity than was common for patients with severe generalized JEB. All this made a precise diagnosis difficult. Clinical case No. 2: an ethnic Russian boy with non-classified JEB. Molecular genetic testing helped to identify a homozygote mutation in the LAMA3 gene that had not been previously described; reliable determination of the subtype was not possible. The patient had mixed clinical manifestation similar both to generalized severe JEB and to laryngo-onycho-cutaneous (LOC) syndrome. During his lifetime, the patient was clinically diagnosed with Hallopeau acrodermatitis and LOC syndrome. The differential diagnostic problems were associated with the presence of signs not typical for each of the subtypes. Significant life longevity of the proband is not characteristic for severe generalized JEB (at the time of the publication the patient is 13 years old), whereas for LOC syndrome the absence of eye involvement is not typical, as well as severe laryngeal involvement at adolescence.Conclusion: Detailed descriptions of phenotype of JEB subtypes including rare and minimal clinical signs can be useful to study the clinical manifestations and natural course of the disease, including its differential diagnosis.

scholarly journals Impaired Mitochondrial and Metabolic Function of Fibroblasts Derived from Patients with Recessive Dystrophic and Junctional Epidermolysis Bullosa

2020 ◽  
pp. 75-83
Author(s):  
Ilona Tietzová ◽  
Kirk Twaroski ◽  
Cindy Eide ◽  
Julie H. Ostrander ◽  
Peter Crawford ◽  
...  
Keyword(s):  
Epidermolysis Bullosa ◽  
Mitochondrial Function ◽  
Metabolic Stress ◽  
Mitochondrial Morphology ◽  
Energy Status ◽  
Inherited Disorders ◽  
Mitochondrial Energy Metabolism ◽  
Junctional Epidermolysis Bullosa ◽  
Skin Fragility ◽  
Skin Healing

Background: Recessive dystrophic epidermolysis bullosa (RDEB) and junctional EB (JEB) are inherited disorders characterised by fragility and blistering of epithelial tissues leading to pain, pruritus, and adherent scarring. The severity and chronic nature of the resultant skin wounds significantly reduces quality and length of life. Current therapies primarily consist of protective bandaging and nutritional supplementation; there is no cure for these disorders. Although the skin fragility results from a lack of C7 protein (RDEB) and laminin-332 (JEB), other serious aspects of these disorders, such as inflammation that interferes with healing and aggressive squamous cell carcinoma, have not been completely elucidated. Recent research has suggested that mitochondrial function plays a significant role in skin healing. Objective: To evaluate how mitochondrial function differs in patients with RDEB and JEB. Method: The energy status of RDEB and JEB patient-derived fibroblasts was determined by Seahorse analysis and metabolite production. The energetics and overall morphology of RDEB and JEB patient-derived fibroblasts were assayed as a measure of metabolic stress. Results: EB patient-derived fibroblasts showed impaired oxidative phosphorylation with concomitant compensation by glycolysis. Morphological parameters were altered in RDEB and JEB fibroblasts compared with controls. Conclusion: This is the first study to describe changes in mitochondrial energy metabolism, metabolic profile, and mitochondrial morphology of EB patients.

Junctional Epidermolysis Bullosa of the Larynx

PEDIATRICS ◽  
1987 ◽  
Vol 79 (6) ◽  
pp. 1051-1052
Author(s):  
ANA GONZALEZ ◽  
LAWRENCE SCHACHNER ◽  
MADELINE MILLER
Keyword(s):  
Respiratory Tract ◽  
Epidermolysis Bullosa ◽  
Autosomal Recessive ◽  
Autosomal Recessive Inheritance ◽  
Skin Lesions ◽  
Genitourinary Tract ◽  
Recessive Inheritance ◽  
Respiratory Compromise ◽  
Junctional Epidermolysis Bullosa ◽  
Laryngeal Involvement

To the Editor.— The article by Kenna et al (Pediatrics 1986;78:172-174) points out the complication of respiratory compromise secondary to laryngeal involvement in junctional epidermolysis bullosa. Junctional epidermolysis bullosa, a mechanobullous disorder with autosomal recessive inheritance, has been associated with not only skin lesions but gastrointestinal, respiratory tract, and genitourinary tract abnormalities as well.1 The figure that was presented in the article incorrectly showed a split in the upper layers of the epidermis inconsistent with junctional epidermolysis bullosa.

scholarly journals Multiple Skin Squamous Cell Carcinomas in Junctional Epidermolysis Bullosa Due to Altered Laminin-332 Function

2020 ◽  
Vol 21 (4) ◽  
pp. 1426
Author(s):  
Paola Fortugno ◽  
Angelo Giuseppe Condorelli ◽  
Elena Dellambra ◽  
Liliana Guerra ◽  
Francesca Cianfarani ◽  
...  
Keyword(s):  
Squamous Cell ◽  
Epidermolysis Bullosa ◽  
Proteolytic Processing ◽  
Disulphide Bond ◽  
Structural Element ◽  
Junctional Epidermolysis Bullosa ◽  
Skin Fragility ◽  
Gene Expression Studies ◽  
Laminin 332

Variably reduced expression of the basement membrane component laminin-332 (α3aβ3γ2) causes junctional epidermolysis bullosa generalized intermediate (JEB-GI), a skin fragility disorder with an increased susceptibility to squamous cell carcinoma (SCC) development in adulthood. Laminin-332 is highly expressed in several types of epithelial tumors and is central to signaling pathways that promote SCC tumorigenesis. However, laminin-332 mutations and expression in individuals affected by JEB-GI and suffering from recurrent SCCs have been poorly characterized. We studied a JEB-GI patient who developed over a hundred primary cutaneous SCCs. Molecular analysis combined with gene expression studies in patient skin and primary keratinocytes revealed that the patient is a functional hemizygous for the p.Cys1171* mutant allele which is transcribed in a stable mRNA encoding for a β3 chain shortened of the last two C-terminal amino acids (Cys1171-Lys1172). The lack of the Cys1171 residue involved in the C-terminal disulphide bond to γ2 chain did not prevent assembly, secretion, and proteolytic processing of the heterotrimeric molecule. Immunohistochemistry of SCC specimens revealed accumulation of mutant laminin-332 at the epithelial-stromal interface of invasive front. We conclude that the C-terminal disulphide bond is a structural element crucial for laminin-332 adhesion function in-vivo. By saving laminin-332 amount, processing, and signaling role the p.Cys1171* mutation may allow intrinsic pro-tumorigenic properties of the protein to be conveyed, thus contributing to invasiveness and recurrence of SCCs in this patient.

scholarly journals YARS2 Missense Variant in Belgian Shepherd Dogs with Cardiomyopathy and Juvenile Mortality

Genes ◽  
2020 ◽  
Vol 11 (3) ◽  
pp. 313
Author(s):  
Corinne Gurtner ◽  
Petra Hug ◽  
Miriam Kleiter ◽  
Kernt Köhler ◽  
Elisabeth Dietschi ◽  
...  
Keyword(s):  
Genetic Defect ◽  
Autosomal Recessive Inheritance ◽  
Missense Variant ◽  
Homozygosity Mapping ◽  
Pedigree Analysis ◽  
Trna Synthetase ◽  
Loss Of Function ◽  
Juvenile Mortality ◽  
Abnormal Accumulation ◽  
The Central Nervous System

Dog puppy loss by the age of six to eight weeks after normal development is relatively uncommon. Necropsy findings in two spontaneously deceased Belgian Shepherd puppies indicated an abnormal accumulation of material in several organs. A third deceased puppy exhibited mild signs of an inflammation in the central nervous system and an enteritis. The puppies were closely related, raising the suspicion of a genetic cause. Pedigree analysis suggested a monogenic autosomal recessive inheritance. Combined linkage and homozygosity mapping assigned the most likely position of a potential genetic defect to 13 genome segments totaling 82 Mb. The genome of an affected puppy was sequenced and compared to 645 control genomes. Three private protein changing variants were found in the linked and homozygous regions. Targeted genotyping in 96 Belgian Shepherd dogs excluded two of these variants. The remaining variant, YARS2:1054G>A or p.Glu352Lys, was perfectly associated with the phenotype in a cohort of 474 Belgian Shepherd dogs. YARS2 encodes the mitochondrial tyrosyl-tRNA synthetase 2 and the predicted amino acid change replaces a negatively charged and evolutionary conserved glutamate at the surface of the tRNA binding domain of YARS2 with a positively charged lysine. Human patients with loss-of-function variants in YARS2 suffer from myopathy, lactic acidosis, and sideroblastic anemia 2, a disease with clinical similarities to the phenotype of the studied dogs. The carrier frequency was 27.2% in the tested Belgian Shepherd dogs. Our data suggest YARS2:1054G>A as the candidate causative variant for the observed juvenile mortality.

Late-onset skin fragility in childhood: a case of junctional epidermolysis bullosa of late onset caused by a missense mutation inCOL17A1

2013 ◽  
Vol 169 (3) ◽  
pp. 714-715 ◽  
Author(s):  
S. Vanotti ◽  
C. Chiaverini ◽  
A. Charlesworth ◽  
N. Bonnet ◽  
P. Berbis ◽  
...  
Keyword(s):  
Missense Mutation ◽  
Epidermolysis Bullosa ◽  
Late Onset ◽  
Junctional Epidermolysis Bullosa ◽  
Skin Fragility
Sign in / Sign up

Export Citation Format

Share Document