Schematic of the <i>LMNA</i> gene and lamin A protein indicating mutations.

<p>(A) Schematic of the <i>LMNA</i> gene and lamin A protein. Lamin A is encoded by exons 1–12, whereas lamin C terminates at exon 10 with six unique amino acids at its C-terminal. The alternative splice site for lamin A is indicated. Sequence variations affecting the splice donor or acceptor sites that lead to disease are shown for IVS-8. Missense mutations and deletions are indicated on the lamin A protein, where the head, central rod, and tail domain (incorporating the nuclear localization signal [NLS], and Ig-like fold) are indicated. Novel sequence variants are shown above the gene/protein. (B) Illustration of the evolutionary conservation of residues associated with novel missense mutations located in the coding region of <i>LMNA</i>. Sequences were obtained from the online database, Swiss-Prot (<a href="http://expasy.org/sprot/" target="_blank">http://expasy.org/sprot/</a>) and aligned using the Align online tool (<a href="http://www.uniprot.org/align/" target="_blank">http://www.uniprot.org/align/</a>).</p

Phenotype and genotype of patients.

<p>p.r.: Previously reported.</p><p>Phenotype and genotype of patients.</p

Muscle cell nuclear morphology.

<p>A, C, D: ×12000; B, E, F, G, H: ×25000. (A, B) Normal control. (C, D, G) Abnormal nuclear morphology. (C, D, F) Heterochromatin condensation (arrows). (E) Focal loss of nuclear membrane (arrows). (G) Nucleolar hole (arrows). (H) Accumulation of mitochondria around nucleus (arrows).</p

Clinical and neuroradiological findings of the patients.

<p>CK = creatine kinase; ECG = electrocardiogram; EMG = electromyogram; MRI = magnetic resonance imaging; UL = upper limb; LL = lower limb; ND = not done.</p><p>Clinical and neuroradiological findings of the patients.</p

Muscle biopsy specimens stained with hematoxylin and eosin.

<p>(A) Normal control (×200). (B) Specimen from patient 11 exhibiting inflammatory cellular infiltration with necrotic and regenerative fibers (×200). (C) Specimen from patient 15 exhibiting mild nuclear transfer and regenerative fibers (×400).</p

Lamin A/C mislocation in mutant-transfected HEK 293 cells.

<p>Transfection was performed using (A) GFP, (B) pEGFP-N1-LMNA, (C) pEGFP-N1-LMNA-R48P, (D) pEGFP-N1-LMNA-R249W, (E) pEGFP-N1-LMNA-I373V, or (F) pEGFP-N1-LMNA-I497_E536del. Lamin A/C of the mutants (C–F) is distributed in clusters and is mislocated compared with that of the wild type (B).</p