Review Charcot-Marie-Tooth Disease
Total Page：16
File Type：pdf, Size：1020Kb
Molecular Medicine 4: 3-11, 1998 Molecular Medicine © 1998 The Picower Institute Press Review Charcot-Marie-Tooth Disease: Lessons in Genetic Mechanisms James R. Lupski Department of Molecular and Human Genetics, Department of Pediatrics, and Texas Children's Hospital, Baylor College of Medicine, Houston, Texas, U.S.A. Introduction weakness that now bears their names. Each rec- ognized the hereditary nature of the disease by In recent years, the application of molecular to more occurrence in sib- techniques to the study of human subjects has pointing the frequent lings and observing the disorder in multiple gen- resulted in a virtual explosion of medical genetic erations in one family. Their observations were information. This information has greatly ex- reported decades before Mendel's laws were re- panded our understanding of disease and the discovered. In 1895 Dejerine and Sottas de- mechanisms that cause them. One example is the molecular dissection of the Charcot-Marie- scribed a more severe neuropathy (3), the Dejer- Tooth (CMT) peripheral neuropathy phenotype. ine-Sottas syndrome (DSS), which was thought The study of CMT has (i) revealed large DNA then to be clinically distinct from CMT. In 1939 Allan (3) used Charcot-Marie-Tooth rearrangements as a frequent mutation mecha- disease, also known as peroneal muscular atro- nism, (ii) illuminated the importance of gene phy, to derive two important principles for clin- dosage as a mechanism, (iii) conceptually fused the seemingly disparate categories of Mendelian ical genetic phenotypes. The first was that differ- disorders and chromosomal syndromes, and (iv) ent patterns of inheritance could be observed in illustrated that both allelic variations and locus disorders thought to be caused by a single defec- tive gene if families were examined. This heterogeneity could be responsible for a spec- enough formulated the concept of ge- trum of clinical phenotypes which may include Allan hypothesis netic heterogeneity (or locus heterogeneity) entities thought to be environmental or ac- quired. This review will briefly summarize what that mutations at different loci could be respon- sible for the same disease in different was known prior to molecular studies, what we phenotype have learned through molecular genetic analysis, families. The second general principle was that age onset and clinical of the dis- and finally, what these lessons mean with re- the of severity spect to other human genetic disorders. ease were somewhat dependent upon the pat- tern of inheritance. Recessive disorders are caused by two mutant genes and have an earlier onset and increased severity when compared What Was Known? with dominant conditions in which only one In 1886, Charcot and Marie (1) in Paris, France gene in a pair is abnormal. and Tooth (2) in Cambridge, England indepen- Throughout the 1960s and 70s, the clinical dently described the disorder of the peripheral details of CMT subtypes and other related pe- nerves that leads to distal muscle atrophy and ripheral neuropathies were elucidated (reviewed in ref. 4). An important clinical observation was Address correspondence and reprint requests to: Dr. James the recognition that two major CMT types could R. Lupski, Baylor College of Medicine, One Baylor Plaza, Room 609E, Houston, TX 77030, U.S.A. Phone: 713-798- be distinguished on the basis of electrophysi- 6530; Fax: 713-798-5073; E-mail: [email protected] ologic and pathologic studies. CMT type 1 4 Molecular Medicine, Volume 4, Number 1, January 1998 (CMT1), which is the demyelinating form pri- The PMP22 gene encoding peripheral myelin marily affecting the glial cells supporting the protein 22, which is mutated in the mouse mod- neuron, is characterized by reduced or slowed els for human demyelinating neuropathies, motor nerve conduction velocities (NCV) and Trembler and Trembler' (15,16), was shown to "onion bulbs" consisting of defective Schwann map within the 1.5 Mb CMT1A duplication/ cell processes on nerve biopsy. In contrast, CMT HNPP deletion region (17-20). The absence of type 2 (CMT2) is characterized by normal or PMP22 point mutation in CMT1A duplication pa- nearly normal NCV with decreased amplitudes tients further supported a gene dosage model reflecting the axonal involvement in this sub- (21). Rare demyelinating neuropathy patients type. without the CMT1A duplication were found to Although the subtypes of CMT could be dis- have PMP22 point mutations, which are usually tinguished clinically and pathologically, it wasn't associated with a more severe CMT1 phenotype until the 1980s that the application of genetic than observed with duplication (22,23). PMP22 linkage analysis enabled the identification of spe- point mutations were also identified in patients cific genetic loci responsible for CMT1 (5-7). with DSS (24). To underscore a PMP22-specific dosage effect, increased levels of PMP22 mRNA were found in biopsied peripheral nerves of pa- tients with the CMT1A duplication (25). Fur- What Have We Learned? thermore, multiple transgenic animals that over- Chromosomal Duplication as a express wild-type PMP22 (26-28), and a PMP22 Mutational Mechanism knockout mouse heterozygous for a PMP22 null The molecular mechanism responsible for the allele (29,30), recapitulated the phenotypic majority of patients with the CMT phenotype properties of the human demyelinating periph- linked to the proximal short arm of chromosome eral neuropathies. Thus, substantial evidence 17 (17pl 1 .2p12) is a submicroscopic DNA dupli- supports the notion that PMP22 is the dosage- cation. This CMT1A duplication is 3 million base sensitive gene responsible for the demyelinating pairs (3 megabases or 3 Mb) in length! It consists phenotype in patients with CMT1A duplication of a duplicated 1.5 Mb monomeric unit, arranged as well as HNPP deletion. This dosage effect is in tandem, and flanked by a 24,000 base pair (24 manifested by either trisomic overexpression in kilobases or 24 Kb) direct repeat, named CMT1A or monosomic underexpression in HNPP CMT1A-REP (8-10). The molecular mechanism (31,32). responsible for the CMT1A duplication is an un- equal crossing-over event mediated by the ho- Bridging the Gap between Chromosomal Syndromes mologous CMTlA-REP repeats. The proposed Disorders mechanism predicted a reciprocal recombination and Mendelian product resulting in a 1.5 Mb deletion (10). This Traditionally, disorders that segregate as Mende- was subsequently shown to be associated with lian traits have been believed to result from mu- the clinically distinct demyelinating peripheral tation in single genes. In contrast, chromosomal neuropathy known as hereditary neuropathy syndromes have been thought to result from ef- with liability to pressure palsies (HNPP) (11,12). fects of many genes within or flanking the region of chromosomal abnormality. Down syndrome associated with trisomy 21 is the most common Gene Dosage as a Mechanism for Disease genetic condition, and yet it has no mutant Several mechanisms were proposed to explain genes; however, a distinct clinical phenotype is how the CMT1A duplication might affect a observed. "CMT1 gene." These included (i) gene interrup- Although the potential effects of gene dosage tion at the duplication junction (most favored by imbalance in chromosomal syndromes had al- this author), (ii) a position effect, and (iii) a gene ready been appreciated (33), the concept of dosage effect due to a dosage-sensitive gene lo- "gene dosage" or gene copy number effects was cated within the duplicated region. The identifi- crystallized by findings at the CMT1A locus. A cation of large, cytogenetically visible chromo- submicroscopic DNA duplication was passed somal duplications of chromosome 17p that through generations as a dominant trait and was contained the CMT1A locus in patients whose responsible for the segregation of the CMT1A phenotype included slowed motor NCV sup- neuropathy phenotype observed by electro- ported the gene dosage model (13,14) (Fig. 1). physiologic studies revealing reduced motor NCV J. R. Lupski: Charcot-Marie-Tooth Disease 5 CHROMOSOMAL 17p SUBMICROSCOPIC C,) ! * CMTlA-REP z 13.3 0 If 13.2 J. 13.1 .1 1* CD 12 J, I CM 11.2 * PMP22 I '"""'; CMTlA-REP 0 6 100kb CMTlA duplication I I CMTlA-REP T 13.3 .1 I .4 CD 13.2 1* I z 0 0 13.1 t I J, I T uJ 12 0 -j I I PMP22 - * LU 11.2 T I I A I CMTlA-REP 100kb HNPP I deletion Fig. 1. Chromosomal syndrome versus Mende- karyogram is an expansion of the submicroscopic lian disorders. In the middle of the figure the G- 17pl2 region with the PMP22 gene (hatched box) banded ideogram for the short arm of chromosome flanked by CMT1A-REP repeats (closed box). The 17-17p is shown; to the left are cytogenetically visi- region duplicated is shown by a bold vertical line ble chromosomal DNA rearrangements, while to the (top right) whereas that deleted is shown by a right are submicroscopic rearrangements. Bold verti- dashed vertical line (bottom right). The asterisk rep- cal rectangles represent the 17p region duplicated resents the point mutation in PMP22 that can be as- (top left), open vertical rectangles show the region sociated with HNPP. deleted (bottom left). Shown to the right of the (34). Likewise, cytogenetically visible chromo- tion that appears mechanistically to occur by somal duplications involving the same region homologous recombination of a flanking repeat presented with the motor NCV abnormality as a gene cluster (39). However, some rare patients distinct part of their more complex phenotype have larger deletions which can include the (35). CMT1A/HNPP genomic region in 17pl2 (40,41). The HNPP deletion is a 1.5 Mb submicro- When SMS patients have a larger deletion that scopic DNA rearrangement. Although as many as includes PMP22, they exhibit eletrophysiologic 30 to 50 genes are likely deleted, only one gene, features consistent with HNPP (40,41). Thus, PMP22, appears to be dosage-sensitive, resulting manifesting a single Mendelian disorder versus a in a haploinsufficiency phenotype.