Mandibuloacral dysplasia in a young Vietnamese girl caused by homozygous missense variant c.1579C>T in the LMNA gene with progeria and severe skin lesions

Variants in the LMNA gene, which encodes Lamin-A/C, have been commonly associated with cardiac conduction system diseases usually accompanying cardiomyopathy. We have seen two unrelated patients who presented with atrioventricular block (AVB) with or without cardiomyopathy. Genetic testing identified the LMNA missense variant c.1634G>A (p.R545H) and the single nucleotide deletion c.859delG (p.A287Lfs*193). The deletion leads to a shift in the reading frame and subsequent protein truncation. Since impaired Nav1.5 function has been reported to cause AVB, we sought to investigate the effects of abnormal Lamins on Nav1.5 in HEK-293 cells using patch-clamp methods. Patch-clamp studies showed that p.R545H decreased the peak INa by approximately 70%. The voltage-dependency of steady state inactivation was rightward shifted in the cells transfected with p.R545H. The p.A287Lfs*193 also decreased the peak INa by approximately 62%. The voltagedependency of steady state inactivation was rightward shifted in the cells transfected with p.A287Lfs*193. Variants of the LMNA gene caused significant reduction of the peak INa in HEK-293 cells, which may account for the patients’ AVB.

Download Full-text

Genome-wide association study of Buruli ulcer in rural Benin

10.1101/19012096 ◽

2019 ◽

Author(s):

Jeremy Manry ◽

Quentin B. Vincent ◽

Maya Chrabieh ◽

Lazaro Lorenzo ◽

Ioannis Theodorou ◽

...

Keyword(s):

Association Study ◽

Odds Ratio ◽

Genome Wide Association Study ◽

Buruli Ulcer ◽

Missense Variant ◽

Skin Lesions ◽

Mycobacterium Ulcerans ◽

Genome Wide Association ◽

Genome Wide ◽

Autophagy Pathway

AbstractBuruli ulcer, caused by Mycobacterium ulcerans, is the third mycobacterial disease worldwide characterized by devastating necrotizing skin lesions. The role of host genetics in susceptibility to Buruli ulcer has long been suggested. We conduct the first genome-wide association study of Buruli ulcer on a combined sample of 1,524 well characterized patients and controls from rural Benin. Two-stage analyses identify two novel associated loci located within lincRNA genes: rs9814705 in ENSG00000240095.1 (P = 2.85×10−7; odds ratio = 1.80 [1.43-2.27]), and rs76647377 in LINC01622 (P = 9.85×10−8; hazard ratio = 0.41 [0.28-0.60]). Furthermore, we replicate the protective effect of allele G of a missense variant located in ATG16L1, and previously shown to decrease bacterial autophagy (rs2241880, P = 0.003; odds ratio = 0.31 [0.14-0.68]). Our results suggest lincRNAs and the autophagy pathway as critical factors in the development of Buruli ulcer.

Download Full-text

Two Decades after Mandibuloacral Dysplasia Discovery: Additional Cases and Comprehensive View of Disease Characteristics

Genes ◽

10.3390/genes12101508 ◽

2021 ◽

Vol 12 (10) ◽

pp. 1508

Author(s):

Isabelle Jéru ◽

Amira Nabil ◽

Gehad El-Makkawy ◽

Olivier Lascols ◽

Corinne Vigouroux ◽

...

Keyword(s):

Phenotypic Variability ◽

Genetic Disorders ◽

Autosomal Recessive Disorder ◽

Missense Variant ◽

Compound Heterozygous ◽

Partial Lipodystrophy ◽

Mandibular Hypoplasia ◽

Pathogenic Variants ◽

Compound Heterozygous Variants ◽

Mandibuloacral Dysplasia

Pathogenic variants in the LMNA gene cause a group of heterogeneous genetic disorders, called laminopathies. In particular, homozygous or compound heterozygous variants in LMNA have been associated with “mandibuloacral dysplasia type A” (MADA), an autosomal recessive disorder, characterized by mandibular hypoplasia, growth retardation mainly postnatal, pigmentary skin changes, progressive osteolysis of the distal phalanges and/or clavicles, and partial lipodystrophy. The detailed characteristics of this multisystemic disease have yet to be specified due to its rarity and the limited number of cases described. Here, we report three unrelated Egyptian patients with variable severity of MAD features. Next-generation sequencing using a gene panel revealed a homozygous c.1580G>A-p.Arg527His missense variant in LMNA exon 9 in an affected individual with a typical MADA phenotype. Another homozygous c.1580G>T-p.Arg527Leu variant affecting the same amino acid was identified in two additional patients, who both presented with severe manifestations very early in life. We combined our observations together with data from all MADA cases reported in the literature to get a clearer picture of the phenotypic variability in this disease. This work raises the number of reported MADA families, argues for the presence of the founder effect in Egypt, and strengthens genotype–phenotype correlations.

Download Full-text

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

Genes ◽

10.3390/genes12091309 ◽

2021 ◽

Vol 12 (9) ◽

pp. 1309

Author(s):

Sarah Kiener ◽

Robert Cikota ◽

Monika Welle ◽

Vidhya Jagannathan ◽

Susanne Åhman ◽

...

Keyword(s):

Plasma Cells ◽

Transmembrane Domain ◽

Clinical Signs ◽

Thick Layer ◽

Missense Variant ◽

Skin Lesions ◽

Acrodermatitis Enteropathica ◽

Loss Of Function ◽

Unrelated Control ◽

Human Phenotype

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).

Download Full-text

Type I interferonopathies with novel compound heterozygous TREX1 mutations in two siblings with different symptoms responded to tofacitinib

Pediatric Rheumatology ◽

10.1186/s12969-020-00490-1 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Shiyu Zhang ◽

Jiaxing Song ◽

Yuyan Yang ◽

Huilei Miao ◽

Lu Yang ◽

...

Keyword(s):

Mutation Screening ◽

Missense Variant ◽

Skin Lesions ◽

Chinese Family ◽

Compound Heterozygous ◽

Therapeutic Effects ◽

Type I ◽

Her Family ◽

Compound Heterozygous Variants ◽

Type I Interferonopathies

Abstract Background Type I interferonopathies are a group of rare autoimmune diseases characterised by excessive activation of type I interferon that leads to disturbances in immune function. Three prime repair exonuclease 1 (TREX1) is an important exonuclease and plays an important role in DNA damage repair. TREX1 mutations are associated with many type I interferonopathies. Studies have been published on the effectiveness of tofacitinib in the treatment of type I interferonopathies. The aim of this study is to identify the pathogenic variation in a Chinese family with type I interferonopathies and to observe the therapeutic effects of tofacitinib. Methods A Chinese family with two members with type I interferonopathies was investigated. Whole exome sequencing and Sanger sequencing were applied for mutation screening using peripheral blood DNA of the patient and her family members. Sequencing results were analysed using bioinformatics software tools including VarCards and PolyPhen-2. Close clinical follow-up and observation were used to record changes in the disease before and after treatment with tofacitinib. Results Compound heterozygous variants of TREX1 were observed in the patient’s genome. One was a missense variant (NM_016381; c.C227T; p.Ala76Val) from the patient’s father, and the other was a frameshift variant (NM_016381; c.458dupA; p.Gln153Glnfs*3) from the patient’s mother. One of the proband’s elder brothers with similar skin lesions also carried these two variants. This brother of the proband had more serious cutaneous involvement with the comorbidity of cerebral palsy. These TREX1 variants have not been reported in previous studies and are predicted to be highly pathogenic. The proband was given tofacitinib that led to a marked improvement. Conclusions We identified two novel complex heterozygous variants in the TREX1 gene, which may underlie the molecular pathogenesis of the type I interferonopathies observed in members of this family. Tofacitinib could be an alternative treatment for this disease.

Download Full-text

Compound Heterozygosity for Mutations in LMNA in a Patient with a Myopathic and Lipodystrophic Mandibuloacral Dysplasia Type A Phenotype

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2007-0116 ◽

2007 ◽

Vol 92 (11) ◽

pp. 4467-4471 ◽

Cited By ~ 41

Author(s):

Francesca Lombardi ◽

Francesca Gullotta ◽

Marta Columbaro ◽

Antonio Filareto ◽

Monica D’Adamo ◽

...

Keyword(s):

Histone H3 ◽

Type A ◽

Lamin A ◽

Tail Domain ◽

Lmna Gene ◽

Partial Loss ◽

Metabolic Complications ◽

Heterochromatin Protein ◽

Normal Expression ◽

Mandibuloacral Dysplasia

Abstract Context: Mandibuloacral dysplasia type A (MADA; OMIM 248370) is a rare progeroid syndrome characterized by dysmorphic craniofacial and skeletal features, lipodystrophy, and metabolic complications. Most Italian patients carry the same homozygous missense mutation (p.R527H) in the C-terminal tail domain of the LMNA gene, which encodes lamin A/C, an intermediate filament component of the nuclear envelope. Objective: The objective of the study was to identify novel LMNA mutations in individuals with clinical characteristics (bird-like facies, mandibular and clavicular hypoplasia, acroosteolysis, lipodystrophy, alopecia) observed in other well-known patients. Design: The LMNA gene was sequenced. Functional properties of the mutant alleles were investigated. Patient: We report a 27-yr-old Italian woman showing a MADA-like phenotype. Features include a hypoplastic mandible, acroosteolysis, pointed nose, partial loss of sc fat, and a progeric appearance. Due to the absence of clavicular dysplasia and normal metabolic profiles, generally associated with muscle hyposthenia and generalized hypotonia, this phenotype can be considered an atypical laminopathy. Results: We identified a patient compound heterozygote for the p.R527H and p.V440M alleles. The patient’s cells showed nuclear shape abnormalities, accumulation of pre-lamin A, and irregular lamina thickness. Lamins A and C showed normal expression and localization. The electron microscopy detected heterochromatin defects with a pattern similar to those observed in other laminopathies. However, chromatin analysis showed a normal distribution pattern of the major heterochromatin proteins: heterochromatin protein-1β and histone H3 methylated at lysine 9. Conclusions: The clinical and cellular features of this patient show overlapping laminopathy phenotypes that could be due to the combination of p.R527H and p.V440M alleles.

Download Full-text

Fine Structural Alterations in Thyroid Follicular Cells (FC) and Changes in Serum Thyroxine Produced by Feeding Polychlorinated Biphenyl (PCB) to Rats

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100079929 ◽

1977 ◽

Vol 35 ◽

pp. 498-499

Author(s):

W.T. Collins ◽

Charles C. Capen ◽

Louis Kasza

Keyword(s):

Feed Efficiency ◽

Polychlorinated Biphenyl ◽

Serum Proteins ◽

Skin Lesions ◽

Hepatic Necrosis ◽

Ultrastructural Changes ◽

Lymphoid Tissues ◽

Heat Transfer Fluids ◽

Thyroid Follicular Cells ◽

Peripheral Metabolism

The widespread contamination of the environment with PCB, a compound used extensively by industry in hydraulic and heat transfer fluids as well as plasticizers and solvents in adhesives and sealants, has resulted in detectable tissue levels in a large portion of the human population, domestic animals, and wildlife. Intoxication with PCB produces severe hepatic necrosis, degeneration of lymphoid tissues and kidney, skin lesions, decreased reproductive performance, reduced feed efficiency, and decreased weight gain. PCB also has been reported to reduce the binding of thyroid hormone to serum proteins and enhance the peripheral metabolism of thyroxine with increased excretion of thyroxine-glucuronide in the bile (Bastomsky, Endocrinology 95: 1150-1155, 1974).The objectives of this investigation were (1) to investigate the histopathologic, histochemical, and ultrastructural changes in thyroid FC produced by the acute (4 week) and chronic (12 week) administration of low (50 ppm) and high (500 ppm) doses of PCB to rats, (2) to correlate these alterations to changes in serum immunoreactive thyroxine concentration, and (3) to investigate the persistence of the effects of PCB on the thyroid gland.

Download Full-text