Introduction
The Charcot-Marie-Tooth (CMT) disorders, also known as “hereditary motor and sensory neuropathies” (HMSNs) form the most common group of inherited neuropathies, affecting 10–40/100,000 individuals. The CMT disorders can be
divided into two subtypes: demyelinating (i.e., type 1, or CMT1) and axonal (i.e., type 2, or CMT2) neuropathies. Genetically, CMT2 is a heterogeneous group of peripheral neuropathies. Seven genes and thirty loci have been reported for CMT1. In contrast, only two specific genes responsible for autosomal dominant CMT2 (AD- CMT2) and one gene for autosomal recessive (AR) CMT2 (AR-CMT2) have been identified. These include mutations in the type IV intermediate filaments (IF) gene neurofilament-light (NF-L) gene, (MIM 162280), microtubule kinesin superfamily member motor protein KIF1Bb (MIM 118210), and the type V nuclear intermediate filament gene LMNA (MIM 150330), which encodes lamins A/C. Besides these mutations, gene defects in MPZ (MIM 118200), which encodes myelin protein zero causes both CMT1 and CMT2 phenotypes.
The mutations in the LMNA gene cause AR-CMT2, which is a rare and severe condition. Clinically, the main symptoms in 90% of cases are early onset of the disease, symmetrical muscle weakness and wasting (predominantly in the distal lower limbs), foot deformities, and walking difficulties associated with reduced or absent tendon reflexes. Confirmation of diagnosis relies essentially on electrophysiology, which shows NCVs 138 m/s at the median nerve, and on histopathology after nerve biopsy, which evidences a loss of myelinated fibers with (for AD-CMT2) or without (for AR-CMT2) regenerative attempts.
The amino acid substitution R298C in LMNA encoding lamins A/C causes AD-CMT2. Mutations in other residues in the LMNA gene cause 13 other diseases, collectively termed laminopathies, including AR-Emery Dreifuss and limb- girdle muscular dystrophies, heart-hand syndrome, dilated cardiomyopathy, partial lipodystrophy, Seip syndrome, diabetes, Mandibuloacral Dysplasia, Hutchison-Gilford and atypical Werner progeria syndromes and Restrictive Dermopathy.
It is still unknown why mutations in specific residues in the lamin A isoforms cause specific diseases and what are the relationship between a specific mutation and the phenotypes that it causes. The structural model suggests that changes in lamin filament assembly causes weakening in the scaffold of nuclei leading to cell death. The gene expression model suggests that specific transcriptional regulators interact with lamins A/C. For example, a specific mutation in lamins A/C causes a loss or abnormal activity of a specific transcriptional regulator and cell death of specific cells. The cell proliferation model suggests that lamins A/C mutations affect the regulation of the cell cycle in specific type of cells .
Mammals have a highly complex nuclear lamina system comprising of 3 lamin genes and probably hundreds of lamin-interacting proteins, which makes the understanding of the molecular basis of CMT2 extremely difficult. In contrast, C. elegans have a simple evolutionarily conserved nuclear lamina. In addition, genetic analysis in C. elegans is relatively simple. Thus, studies of lamin in C. elegans can address fundamental questions regarding: why mutations in lamins cause death of nerve cells, which transcriptional regulators in the nerve cell require R298 for its interaction, do nerve cell nuclei change their shape due to CMT2 mutations and how lamin assembly into filaments is affected by the R298C mutation. The combined research in mammalian cells and in C. elegans should provide a
better understanding of the disease and will suggest ways for treating it.
Another complication to the story of laminopathic diseases is the fact that mutations in lamin cause abnormal post-translational modifications of its carboxyl terminus, leaving a fraction of farnesylated molecules.
Jacques & Adela Kluger Memorial for ALS Research
