Genetics and pathomechanism

E. Nelis, P. de Jonghe, V. Timmerman

6.2 Autosomal recessive demyelinating CMT

6.2.4 Genetics and pathomechanism

Extremely rapid progress in the identification of the genetic defects caus-ing the recessive types of CMT has been made in the last three years. This rapid progress is, on the one hand, due to technology improvement and the availability of the human genome sequence but, on the other hand, also caused by the fact that homozygosity mapping often permits the delinea-tion of very small candidate regions. Currently only one genetically mapped subtype with unknown genetic cause remains.

z CMT4A ± ganglioside-induced differentiation associated protein 1 gene (GDAP1) (OMIM 214400)

CMT4A was identified in Tunisian families and maps to chromosome 8q13-q21 [10]. CMT4A is caused by point mutations in the ganglioside-in-duced differentiation associated protein 1 gene (GDAP1) and a Hispanic founder mutation for some families has been identified [8, 21]. Interest-ingly a locus for axonal AR CMT with pyramidal features was mapped to chromosome 8q21.3 [7]. This locus was also mapped in an inbred Tunisian family and overlaps with the CMT4A locus. This raises the possibility that this axonal AR CMT form and demyelinating CMT4A could be allelic. The finding of mutations in GDAP1 in families displaying an axonal type of CMT (CMT4C4) associated with vocal cord paresis supports this hypot-hesis [31]. Furthermore, GDAP1 mutations are also identified in CMT pa-tients with both demyelinating and axonal features [1, 98, 132]. GDAP1 had been cloned in a screen for genes that are involved in ganglioside-in-duced differentiation of a mouse neuroblastoma cell line [80]. GDAP1 is 6 Charcot-Marie-Tooth disease type 1 and hereditaryneuropathywith liabilityto pressure palsy z 105

expressed in brain and peripheral nerve. The exact function of GDAP1 in the PNS needs to be determined. It might be involved in neural differentia-tion [80]; however, the glutathione S-transferase domain points to a func-tion in detoxificafunc-tion and protecfunc-tion against free radicals [128].

z CMT4B1 ± myotubularin related protein 2 gene (MTMR2) (OMIM 601382)

CMT4B1 is caused by point-mutations in the myotubularin related protein 2 gene (MTMR2) on chromosome 11q23 [23, 24, 56, 97]. Some mutations are found in patients with a very severe phenotype, diagnosed as CH. Mu-tations in the myotubularin gene (MTM1), which is the first cloned mem-ber of this gene family, cause X-linked recessive myotubulary myopathy [73]. The MTM1 and MTMR2 genes code for tyrosine phosphatases which influence transcription and cell proliferation [32]. MTMR2 physically inter-acts with the NEFL protein which is mutated in CMT2E, but the function of this interaction is yet unknown [118].

z CMT4B2 ± myotubularin related protein 13 gene (MTMR13 orSBF2) (OMIM 604563 and 607739)

CMT4B2 was found in Tunisian families and maps to chromosome 11p15 [11]. Two groups identified causative mutations in a novel gene of the MTMR family named MTMR13 or set binding factor 2 (SBF2) [6, 134].

Mutations in MTMR13 in the original family described by Ben Othmane have not yet been reported [11]. MTMR13 is a catalytically inactive mem-ber of the MTM gene family that might be involved in the regulation of ac-tive family members. MTMR13/SBF2 is expressed in multiple tissues, in-cluding brain and sciatic nerve [6].

z CMT4C ± unknown transcript KIAA1985 (OMIM 601596)

The CMT4C locus on chromosome 5q23-q33 was identified in two Algerian families [77]. Causative mutations have been identified in a novel tran-script of yet unknown function called KIAA1985 [133]. Mutations in the originally linked families have not been reported. KIAA1985is strongly ex-pressed in neural tissues, including peripheral nerve tissue. The translated protein defines a new protein family of unknown function with putative orthologues in vertebrates. Comparative sequence alignments indicate that members of this protein family contain multiple sarc homology (SH3) and tetratricopeptide repeat (TPR) domains that are likely involved in the for-mation of protein complexes.

z CMT4D synonymous to HMSN-Lom ± N-myc downstream regulated gene 1 (NDRG1) (OMIM 601455)

In HMSN-L (CMT4D) families, linkage to chromosome 8q24 was found.

Conserved disease haplotypes suggested genetic homogeneity and a single founder mutation [64]. Mutation analysis of the N-myc downstream regu-lated 1 gene (NDRG1) revealed a homozygous nonsense mutation in all pa-tients [63]. The exact function of NDRG1 is unknown. Computer analysis has predicted that the NDRGs belong to the a/b hydrolase superfamily;

however they do not appear to be active hydrolases [138]. NDRG1 is ex-pressed in multiple tissues including Schwann cells and probably plays a role in growth control and cell differentiation. Only recently, a second NDRG1 mutation was identified [57].

CMT4E, often presenting as CH, is caused by recessive mutations in the EGR2 gene, which is discussed in detail in the section on ªCMT1Dº in this chapter.

z CMT4F ± periaxin gene (PRX) (OMIM 605725)

A CMT4F locus on chromosome 9p13 was found in a Lebanese family with a severe CMT1 phenotype [38], and a mutation in PRX was identified in this family [51]. PRX mutations were also identified in patients with a DSS or CMT1 phenotype [22, 148]. The pathogenesis of PRX mutations is not fully understood. However, progress is being made by studying both the periaxin-null mouse and the protein-protein interactions of periaxin. L-periaxin is a constituent of the dystroglycan-dystrophin-related protein-2 complex linking the Schwann cell cytoskeleton to the extracellular matrix.

Although periaxin-null mice myelinate normally, they develop a demyeli-nating peripheral neuropathy later in life. This suggests that periaxin is re-quired for the stable maintenance of a normal myelin sheath. Sciatic nerve crushes in periaxin-null mice and showed that although the number of myelinated axons had returned to normal, the axon diameters remained smaller than in the contralateral uncrushed nerve. Not only do periaxin-null mice have more hyper-myelinated axons than their wildtype counter-parts but they also recapitulate this hypermyelination during regeneration.

Therefore, periaxin-null mice can undergo peripheral nerve remyelination, but the regulation of peripheral myelin thickness is disrupted [50, 168].

z Congenital cataract facial dysmorphism neuropathy (CCFDN) ± C-terminal domain phosphatase of RNA polymerase II gene (CTDP1) (OMIM 604186)

CCFDN was identified in 19 Wallachian Gypsy families and mapped to chromosome 18qter [3]. A conserved haplotype suggested a single founder mutation. CCFDN is caused by a single-nucleotide substitution in an anti-sense Alu element in intron 6 of CTDP1, an essential component of the eu-6 Charcot-Marie-Tooth disease type 1 and hereditaryneuropathywith liabilityto pressure palsy z 107

karyotic transcription machinery, resulting in a rare mechanism of aber-rant splicing and an Alu insertion in the processed mRNA. CCFDN thus joins the group of `transcription syndromes' and is the first `purely' tran-scriptional defect identified that affects polymerase II-mediated gene ex-pression. A clinically sometimes very similar disease is Marinesco-Sjogren syndrome, distinguished from CCFDN by its genetic locus on chromosome 5q31 [70].

z Recessive mutations in the peripheral myelin protein 22 gene (PMP22) and the myelin protein zero gene (MPZ)

In a few cases, recessive mutations are found in genes for dominant forms of CMT1. In PMP22, a single homozygous missense mutation was found in 3 sibs with DSS. The parents, carrying the mutation in the heterozygous state, are clinically and electrophysiologically unaffected [110]. Two hemi-zygous PMP22 point mutations were described in CMT1 patients. Individ-uals heterozygous for the mutation are unaffected, while individIndivid-uals with a PMP22 deletion on the other allele have a CMT1 phenotype [103, 125]. It is still controversial if these PMP22 mutations represent recessive CMT1 mutation or functionally irrelevant polymorphisms [100, 179]. Several MPZ mutations occur in the heterozygous as well as in the homozygous/com-pound heterozygous state. The heterozygous individuals are asymptomatic or have CMT1, while the homozygous/compound heterozygous individuals are severely affected, mostly they are diagnosed as DSS [58, 74, 116, 165].

z HMSN-Russe ± chromosome 10q22

CMT Russe (HMSN-R) is linked to chromosome 10q22 [52, 126]. Fine mapping reduced the critical candidate region to only 70 kb [52]. The fact that no sequence variant has been detected in the known genes in the criti-cal region indicates that the HMSN-R mutation affects a novel gene that re-mains to be identified.

z Acknowledgements

Our research is funded by grants of the Fund for Scientific Research ± Flanders (FWO-Vlaanderen), the Special Research Fund of the University of Antwerpen, the Medical Foundation Queen Elisabeth, the Association Belge contre les Maladies Neuro-Musculaires, the Interuniversity Attraction Poles program P5/19 of the Belgian Federal Science Policy Office (Belgium) and the Muscular Dystrophy Association (USA). EN is a postdoctoral fellow of the FWO-Vlaanderen.

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