LMNA mutations in atypical Werner's syndrome

Autor:	Yousef Shafeghati, Junko Oshima, Abhimanyu Garg, Eleanor G. Botha, Brian K. Kennedy, Heloísa G. dos Santos, Nancy B. Hanson, Lin Lee, George M. Martin, Olav Sletvold, Lishan Chen, I. Saira Mian, Brian A. Kudlow
Rok vydání:	2003
Předmět:	Male congenital hereditary and neonatal diseases and abnormalities Werner Syndrome Helicase Adolescent DNA Mutational Analysis Mutation Missense Laminopathy Biology Progeroid syndromes LMNA medicine Humans Missense mutation RNA Messenger Registries Atypical Werner syndrome Child education Cells Cultured Werner's syndrome Werner syndrome Genetics education.field_of_study RecQ Helicases integumentary system Reverse Transcriptase Polymerase Chain Reaction DNA Helicases Nuclear Proteins nutritional and metabolic diseases Exons General Medicine Fibroblasts Lamin Type A medicine.disease Pedigree Exodeoxyribonucleases Mutation Female Werner Syndrome
Zdroj:	The Lancet. 362:440-445
ISSN:	0140-6736
DOI:	10.1016/s0140-6736(03)14069-x
Popis:	Summary Background Werner's syndrome is a progeroid syndrome caused by mutations at the WRN helicase locus. Some features of this disorder are also present in laminopathies caused by mutant LMNA encoding nuclear lamin A/C. Because of this similarity, we sequenced LMNA in individuals with atypical Werner's syndrome (wild-type WRN ). Methods Of 129 index patients referred to our international registry for molecular diagnosis of Werner's syndrome, 26 (20%) had wildtype WRN coding regions and were categorised as having atypical Werner's syndrome on the basis of molecular criteria. We sequenced all exons of LMNA in these individuals. Mutations were confirmed at the mRNA level by RT-PCR sequencing. In one patient in whom an LMNA mutation was detected and fibroblasts were available, we established nuclear morphology and subnuclear localisation. Findings In four (15%) of 26 patients with atypical Werner's syndrome, we noted heterozygosity for novel missense mutations in LMNA, specifically A57P, R133L (in two people), and L140R. The mutations altered relatively conserved residues within lamin A/C. Fibroblasts from the patient with the L140R mutation had a substantially enhanced proportion of nuclei with altered morphology and mislocalised lamins. Individuals with atypical Werner's syndrome with mutations in LMNA had a more severe phenotype than did those with the disorder due to mutant WRN. Interpretation Our findings indicate that Werner's syndrome is molecularly heterogeneous, and a subset of the disorder can be judged a laminopathy.
Databáze:	OpenAIRE
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