Homozygous Defects in LMNA, Encoding Lamin A/C Nuclear-Envelope Proteins, Cause Autosomal Recessive Axonal Neuropathy in Human (Charcot-Marie-Tooth Disorder.

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Homozygous Defects in LMNA, Encoding Lamin A/C Nuclear-Envelope Proteins, Cause Autosomal Recessive Axonal Neuropathy in Human (Charcot-Marie-Tooth Disorder Type 2) and Mouse Annachiara De Sandre-Giovannoli, Malika Chaouch, Serguei Kozlov, Jean-Michel Vallat, Meriem Tazir, Nadia Kassouri, Pierre Szepetowski, Tarik Hammadouche, Antoon Vandenberghe, Colin L. Stewart, Djamel Grid, Nicolas Lévy The American Journal of Human Genetics Volume 70, Issue 3, Pages 726-736 (March 2002) DOI: 10.1086/339274 Copyright © 2002 The American Society of Human Genetics Terms and Conditions

Figure 1 Ultrastructural micrograph of peripheral nerve from an individual from family ALG.16-301 who is affected with CMT2. A severe rarefaction of myelinated and nonmyelinated fibers can be observed. Large myelinated fibers are almost totally lacking. Neither onion bulbs (proliferations of Schwann cells) nor regenerating clusters are present. Nerve biopsies were performed, and the samples were prepared for electron microscopy as described elsewhere (Hahn et al. 2001). The American Journal of Human Genetics 2002 70, 726-736DOI: (10.1086/339274) Copyright © 2002 The American Society of Human Genetics Terms and Conditions

Figure 2 Pedigree of largest Algerian family with AR-CMT2, mutant haplotypes, and integrated map at the LMNA locus. A, Pedigrees and genotypes of Algerian families ALG.16-301 and ALG.16-315, both with AR-CMT2. Blackened symbols represent subjects with clinical, electrophysiological, and histological diagnosis of CMT2. The homozygosity interval in each affected individual is boxed and shaded. B, Genetic, physical, and partial transcriptional map of 1q21.2-q21.3 region. The common haplotype for D1S303, D1S2777, and D1S2721 that is shared by all affected individuals from the three Algerian families is shown (see “Results” section). Position of genetic markers is indicated with two-point LOD-score values. The positions of A1U, SEMB, and LMNA are indicated. The American Journal of Human Genetics 2002 70, 726-736DOI: (10.1086/339274) Copyright © 2002 The American Society of Human Genetics Terms and Conditions

Figure 3 Lamin A/C R298C mutation. A, Sequence analysis and identification of R298C mutation in LMNA. DNA sequences from normal control (+/+), unaffected heterozygote (+/−), and homozygote (−/−) are presented. The R→C amino acid substitution at position 298 of human lamin A/C peptidic sequence is indicated. B, Segregation of the nucleotidic 892C→T mutation in a branch of family ALG.16-301 assayed by digestion with AciI. The 306-bp PCR product encompassing exon 5 includes one invariant AciI restriction site in wild-type alleles, which disappears when transition C→T is present, thereby leading to a 306-bp digestion fragment compared with the 126-bp and 180-bp bands observed for the wild-type allele. Normal (n) and mutant (m) fragments, as well as the mutation status (+/+, +/−, and −/−), are indicated for each individual. Undigested and digested fragment sizes, respectively, are 40 and 20 bp larger than described, owing to the M13 universal and reverse primers' sequencing tags (see “Subjects and Methods” section). The American Journal of Human Genetics 2002 70, 726-736DOI: (10.1086/339274) Copyright © 2002 The American Society of Human Genetics Terms and Conditions

Figure 4 Alignment of amino acid sequence of human lamin A/C with its orthologs from various species and human lamin B1, showing conservation of arginine at position 298. Fully conserved amino acids are shown atop a shaded background. The conservation of arginine at position 298 and its substitution in patients with AR-CMT2 are shown in boldface. The DNA sequences encoding the normal and mutant proteins are shown above and below the amino acid sequences, respectively. The American Journal of Human Genetics 2002 70, 726-736DOI: (10.1086/339274) Copyright © 2002 The American Society of Human Genetics Terms and Conditions

Figure 5 Electron micrographs from transverse sections of sciatic nerves of Lmna knockout and control mice at age 7 wks. A, Sciatic nerve of Lmna +/+ control. B, Sciatic nerve of Lmna +/− mouse. No abnormality was detected, although a slight accumulation of neurofilaments was observed. Axon density, size, and myelination were preserved. C, Sciatic nerve of Lmna −/− mouse. Axon density was reduced, and several pathological axons are indicated by asterisks (*). The axons' diameters are enlarged, and no myelin sheath is visible; additionally, they present focal accumulations of neurofilaments, as observed in nerves of Lmna +/− mouse (bars correspond to 1 μm). The American Journal of Human Genetics 2002 70, 726-736DOI: (10.1086/339274) Copyright © 2002 The American Society of Human Genetics Terms and Conditions