Diagnostic Exome Sequencing Identifies a Novel Gene, EMILIN1, Associated with Autosomal‐Dominant Hereditary Connective Tissue Disease

Autor: Paola Spessotto, Francesco Bucciotti, Peter J. Hulick, Roberto Doliana, Cameron Mroske, Qingshen Gao, Kelly D. Farwell, Brigette Tippin Davis, Alfonso Colombatti, Scott M. Weissman, Alessandra Capuano
Jazyk: angličtina
Rok vydání: 2015
Předmět:
0301 basic medicine
Proband
Male
Pathology
Connective Tissue Disorder
Biopsy
DNA Mutational Analysis
Gene Expression
Mice
EMILIN‐1
Cluster Analysis
Exome
Connective Tissue Diseases
Genetics (clinical)
Exome sequencing
Research Articles
connective tissue
Genes
Dominant
Skin
Genetics
Sanger sequencing
Membrane Glycoproteins
High-Throughput Nucleotide Sequencing
Connective tissue disease
Magnetic Resonance Imaging
diagnostic exome sequencing
Pedigree
medicine.anatomical_structure
Phenotype
symbols
Female
Research Article
medicine.medical_specialty
Molecular Sequence Data
Connective tissue
Biology
Cell Line
03 medical and health sciences
symbols.namesake
autosomal dominant
medicine
Animals
Humans
Amino Acid Sequence
EMILIN1
Computational Biology
medicine.disease
030104 developmental biology
Mutation
biology.protein
neuropathy
Elastin
Sequence Alignment
Zdroj: Human Mutation
ISSN: 1098-1004
1059-7794
Popis: Heritable connective tissue diseases are a highly heterogeneous family of over 200 disorders that affect the extracellular matrix. While the genetic basis of several disorders is established, the etiology has not been discovered for a large portion of patients, likely due to rare yet undiscovered disease genes. By performing trio‐exome sequencing of a 55‐year‐old male proband presenting with multiple symptoms indicative of a connective disorder, we identified a heterozygous missense alteration in exon 1 of the Elastin Microfibril Interfacer 1 (EMILIN1) gene, c.64G>A (p.A22T). The proband presented with ascending and descending aortic aneurysms, bilateral lower leg and foot sensorimotor peripheral neuropathy, arthropathy, and increased skin elasticity. Sanger sequencing confirmed that the EMILIN1 alteration, which maps around the signal peptide cleavage site, segregated with disease in the affected proband, mother, and son. The impaired secretion of EMILIN‐1 in cells transfected with the mutant p.A22T coincided with abnormal protein accumulation within the endoplasmic reticulum. In skin biopsy of the proband, we detected less EMILIN‐1 with disorganized and abnormal coarse fibrils, aggregated deposits underneath the epidermis basal lamina, and dermal cells apoptosis. These findings collectively suggest that EMILIN1 may represent a new disease gene associated with an autosomal‐dominant connective tissue disorder.
Databáze: OpenAIRE
Externí odkaz: