Brain, Vol. 124, No. 5, 907-915,
May 2001
© 2001 Oxford University Press
Mutations in the 5' region of the myotubularin-related protein 2 (MTMR2) gene in autosomal recessive hereditary neuropathy with focally folded myelin
1 University Department of Clinical Neurology and 2 Department of Clinical Neurosciences, Royal Free and University College Medical School, London, UK
Correspondence to:
Professor P. K. Thomas, University Department of Clinical Neurology, Institute of Neurology, Queen Square, London WC1N 3BG, UK E-mail: pkthotline{at}virgin.net
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Abstract |
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Focally folded myelin has been recognized as a distinctive feature in some individuals with severe inherited demyelinating neuropathy, with an onset in childhood. Such cases have been shown to be genetically heterogeneous. Alterations in the myotubularin-related protein 2 (MTMR2) gene on chromosome 11q22 have recently been shown to give rise to this phenotype. Mutations have been identified in the 3' region of the MTMR2 gene in four unrelated families, in two of whom the disorder had been mapped to chromosome 11q22 by genetic linkage analysis. We have sequenced the entire coding region and flanking intronic regions of the MTMR2 gene in eight families with early onset autosomal recessive neuropathies. Two novel mutations were identified in exon 4 at the 5' end of the MTMR2 gene in an English and an Indian family. The clinical phenotype and sural nerve pathology in these two families differs in severity, with the proband in the English family having an earlier onset and more severe neuropathy with prominent cranial nerve involvement. This is probably due to mutation type and possible involvement of small nucleotide polymorphisms in phenotype modulation. Detailed sural nerve pathology is presented in both cases. Mutations in the MTMR2 gene are thus an important cause of autosomal recessive demyelinating neuropathy. Identifying further mutations and defining their phenotype will help to clarify the genetic classification of this group of disorders.
Charcot-Marie-Tooth disease; dysmyelination; hereditary neuropathy
CMT = Charcot–Marie–Tooth disease; HMSN = hereditary motor and sensory neuropathy; ; MPZ = myelin protein zero; MTMR2 = myotubularin-related protein 2; PCR = polymerase chain reaction; SNP = small nucleotide polymorphism
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Introduction |
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Considerable advances been made in recent years into the molecular genetics of the hereditary motor and sensory neuropathies (HMSN), especially with autosomal dominant and X-linked recessive inheritance (Reilly, 2000
), and this is now extending to autosomal recessive inheritance (Thomas, 2000). For clinical purposes it is still useful to distinguish those with a demyelinating neuropathy (HMSN I) from those with an axonal neuropathy (HMSN II) (Dyck and Lambert, 1968a, b), although the disability in both is primarily related to axon loss. The demyelinating neuropathies can show distinctive structural features, one of which is the presence of focal myelin enlargements (tomacula) that are encountered in hereditary neuropathy with liability to pressure palsies (Behse et al., 1972; Madrid and Bradley, 1975) and other disorders. Tyson et al. (1997) analysed a series of cases of severe hereditary demyelinating neuropathy with an onset in childhood and showed that they were clinically heterogeneous. Two unrelated cases in this series, both with autosomal recessive inheritance, showed focally folded myelin sheaths on nerve biopsy.
The first recognition of neuropathy with focally folded myelin was by Ohnishi et al. (1989), and subsequently by Gabreëls-Festen et al. (1990) and others, in families showing autosomal recessive inheritance. The condition is now known to be genetically heterogeneous. Families have been mapped to chromosome 11q22, referred to as Charcot–Marie–Tooth disease 4B1 (CMT4B1) (Bolino et al., 1996; Quattrone et al., 1996; Gambardella et al., 1998) and chromosome 11p15 (CMT4B2) (Ben Othmane et al., 1999). Mutations in the gene for myotubularin-related protein 2 (MTMR2) have recently been identified by positional cloning in four families with neuropathy with focally folded myelin, mapping to chromosome 11q22 (CMT4B1) (Bolino et al., 2000a, b). The families all displayed autosomal recessive inheritance and were from Italy and Saudi Arabia. Mutations were not found in a further Italian patient and in a Polish kindred in whom linkage to chromosome 11q22 had been established (Bolino et al., 2000a, b). These patients may have had mutations in the promoter region of the gene, which was not analysed.
It is now clear that mutations in the same gene can give rise to markedly different phenotypes. Thus mutations in the gene for myelin protein zero (MPZ) usually cause an autosomal dominant demyelinating neuropathy referred to as HMSN Ib, but occasionally an axonopathy with the features of HMSN II is produced (Marrosu et al., 1998). We have therefore screened eight families with neuropathies for mutations in the MTMR2 gene. In the majority of them the parents were consanguineous, and in the other families the pattern of inheritance was consistent with autosomal recessive transmission. In two families, sural nerve biopsy had demonstrated focally folded myelin (see Table 1).
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Material and methods |
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Genetic sequencing
Ethical approval was obtained from the National Hospital for Neurology and Neurosurgery Ethics Committee for research into neuropathy. DNA was extracted from blood samples obtained with informed consent from affected and unaffected individuals from families with autosomal recessive neuropathies (Table 1
). Clinical details, the results of nerve conduction studies and those for nerve biopsy if carried out were obtained in all cases included in the study. Chromosome 17 duplication was excluded in all families. The MPZ gene was sequenced in the two families with focally folded myelin and was found not to carry mutations. The 18 exons and flanking intronic regions of the MTMR2 gene were amplified by the polymerase chain reaction (PCR) using primers reported by Bolino et al. (2000a, b). PCR was carried out in a total volume of 50 µl, which contained 20 ng of DNA, 0.2 mM dNTPs, 1 U TaqGold polymerase, 1.5 mM MgCl2, 75 mM Tris–HCl pH 9.0, 20 mM (NH4)2SO4, 0.01% Tween 20 and 50 pmol of each primer. PCR was performed on a Perkin-Elmer 9700 thermal Cycler (Perkin-Elmer, Applied Biosystems, Foster City, Calif., USA). The cycling consisted of denaturation at 94°C for 15 min, followed by 25 cycles of 94°C for 30 s, 60°C to 50°C touching down protocol for 30 s and 72°C for 30 s. After that, 12 cycles of constant annealing temperature at 50°C and a final amplification at 72°C for 10 min were carried out. PCR fragments were checked on a 1% agarose gel. The PCR products were puri- fied by using a Qiaquick purification kit (Qiagen, Hilden, Germany) and resuspended in 50 µl of deionized water. For each exon, 100 ng of amplified product was sequenced using forward and reverse primers and the BigDye Terminator cycle sequencing kit (Perkin-Elmer). Sequencing was performed on an ABI377 automated sequencer. Sequence alignment and analysis was carried out using a Sequence Navigator (Perkin-Elmer).
Mutation and polymorphism analysis
In addition to the two pathogenic mutations, a number of small nucleotide polymorphisms (SNPs) were identified throughout the MTMR2 gene (Table 2). None of the mutations or SNPs created restriction enzyme cut sites that could allow clear differentiation between the presence or absence of the mutation or SNPs. We therefore had to sequence the relevant MTMR2 exons in family members to look for segregation and controls to analyse SNP frequency. A pentanucleotide repeat of ATTTT was identified in the 3' region of MTMR2 exon 2b at –3 bp (Table 2). To analyse the number of repeats, the MTMR2 exon 2b primers were labelled with a fam fluorescent tag. The PCR protocol was the same as for sequencing of the MTMR2 gene except that the reaction volume was 7.5 µl. The PCR was checked on a 1% agarose gel. This marker was diluted and pooled according to protocol (ABI Linkage Mapping Set version 2.0) and run on a 377 ABI sequencer using Genescan software to identify marker alleles. These data were analysed and alleles typed using ABI Genotyper software.
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Mutation segregation
To look for segregation of the disease in an autosomal recessive pattern, four polymorphic repeat markers close to the MTMR2 gene were analysed in the two families thought to have mutations (Table 1
). These fluorescence-labelled markers were D11S937, D11S4175, D11S898 and D11S908. The protocol for analysis of these markers is the same as that for the MTMR2 pentanucleotide repeat detailed above.
Sural nerve biopsy
Sural nerve fascicular biopsies were obtained from a standard retromalleolar site. Following routine aldehyde fixation, post-osmication, dehydration through an ascending alcohol series and resin embedding, semi-thin sections were stained with thionin and acridine orange (Sievers, 1971). Ultrathin sections for electron microscopy were contrasted with uranyl acetate and lead citrate. Teased fibre preparations were obtained by the method described by Spencer and Thomas (1970).
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Results |
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Two novel MTMR2 mutations were identified; these were not present in 80 English and 20 Indian controls (Fig. 1A and B
). No pathogenic mutations were detected in the other six families although a number of novel polymorphisms were identified (Table 2). Two of the polymorphisms were not present in controls. The 3' +12 bp C
T change in exon 1 did not segregate with the disease within the family, indicating a non-pathogenic change. The 3' +31 bp GA change in exon 2A found in family C is discussed further below.
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Family C
This family was of English origin and the proband's parents were second cousins (Fig. 2A
). A homozygous GA mutation was detected in exon 4 of the MTMR2 gene, changing glycine to glutamic acid at codon 103. The mutation and polymorphic markers close to the gene segregated with the disease in family C (Figs 1B and 2A). A sequence variant changing a G to an A in exon 2a +31 bp 3' also segregated with the disease in this family; this change is likely to be in linkage disequilibrium with the exon 4 mutation, but may modulate the phenotype. The variant was not present in 20 controls. This change did not affect the splicing of this exon or create an aberrant splice site when analysed using the splice prediction program RNAfold, although this does not rule out the possibility that the variant induces abnormal splicing.
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The clinical features of this patient have been reported previously by Tyson and colleagues (Tyson et al., 1997
) (Case 9), therefore only a summary is given here. Case 9 was noticed to have an abnormal cry at birth but his early developmental milestones were normal. Difficulty with gait was evident when he began walking at the age of 13 months, but did not become prominent until the age of 3 years when he was found to have hypotonic muscle weakness in the limbs and to be areflexic. Vocal cord paralysis with stridor then appeared, as did difficulty with phonation, chewing and swallowing. The limb weakness increased and he has been confined to a wheelchair since the age of 16 years. Diaphragmatic weakness has also developed so that he requires NIPPV (non-invasive positive pressure ventilation) at night. Examination showed bilateral facial and jaw weakness, tongue wasting, mild stridor and dysarthric speech. There was diffuse upper limb weakness, diaphragmatic weakness and total hypotonic paralysis in the legs. He was areflexic and showed distal sensory impairment in the limbs. Electromyography demonstrated widespread denervation, absent sensory action potentials and a motor conduction velocity of 16 m/s in the ulnar nerve.
Family V
This family was of Indian origin. Both the parents and the paternal grandparents were first cousins (Fig. 2B). A homozygous deletion of an A at base 324 causing a frameshift mutation was detected. This mutation created a premature stop site in mRNA and hence a truncated protein (Fig. 1A).
The clinical features of this patient have also been reported by Tyson and colleagues (Tyson et al., 1997) (Case 8) and therefore only a summary is given here. Case 8 began to walk at 12 months of age but he progressively developed bilateral footdrop; manual dexterity was observed to be poor and his speech was slightly indistinct. Examination showed mild dysarthria, distal upper limb and anterolateral lower leg muscle wasting, weakness and tendon areflexia. No sensory loss was detected. Sensory nerve action potentials were absent. Motor nerve conduction velocity was 15 and 17 m/s in the ulnar and median nerves, respectively.
Nerve biopsy findings
Cases 9 (family C) and 8 (family V) appeared to be similar. There was a severe loss of myelinated fibres, the density in Case 9 being 910/mm2 and 3096/mm2 in Case 8 (normal range for this age group, 8000–11 000/mm2; Jacobs and Love, 1985). Surviving myelinated fibres were generally hypomyelinated, but showed focal regions where the myelin was thrown into irregular protrusions from the outer aspect of the myelin sheath or which occasionally arose from the adaxonal aspect of the sheath (Fig. 3). Transverse electron microscope sections through such regions demonstrated that some of these outpouchings contained axonal protrusions, whereas others contained Schwann cell cytoplasm (Fig. 4). The presence of circumferential Schwann cell processes and basal lamina around some fibres (Fig. 5) indicated the occurrence of repeated episodes of demyelination and remyelination. Longitudinal electron microscope sections showed that at the nodes of Ranvier the Schwann cell nodal processes were often deficient (Fig. 5). Teased fibre studies revealed the presence of multiple myelin thickenings superficially resembling tomacula, but which were smaller in diameter and more irregular in contour (Fig. 6). These were present on all large and medium calibre fibres but could not be detected on small diameter fibres because of poor myelin staining.
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Discussion |
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We have identified two pathogenic mutations in the 5' end of the MTMR2 gene in an English and an Indian family, both with autosomal recessive inheritance, with hereditary neuropathy with focally folded myelin. We also sequenced the MTMR2 gene in six other families with autosomal recessive neuropathies, but no pathogenic mutations were identified in these kindreds, suggesting the presence of other genes for autosomal recessive neuropathy. This finding extends the spectrum of mutations in this gene to both 3' and 5' regions of the MTMR2 gene. The mutations severely disrupt the gene and are either deletions, insertions or complex rearrangements, although we identified a missense change in the English family. The mutations that disrupt the gene are likely to result in loss of function of the protein by significantly altering its structure or disrupting splicing. This occurs in the Indian family V, where the mutation causes a truncated protein. The missense mutation of a glycine to glutamic acid at codon 103 in family C causes an identical severe clinical and pathological phenotype to that of other CMT 4B families, and this mutation is also likely to cause loss of function by substituting a key amino acid in the protein, rendering it inactive. MTMR2 is a protein tyrosine phosphatase and may act to dephosphorylate its target substrate in a similar fashion to the myotubularin (MTM1) gene in X-linked myotubular myopathy (Laporte et al., 1996
, 1998; Cui et al., 1998). The lack of MTMR2 is likely to lead to overactivity of the substrate, but how this results in demyelination and focal folding of the myelin sheaths is as yet uncertain. It is clear that focal folding of the myelin is not a specific morphological change. Apart from CMT4B1 and CMT4B2, it has been observed in a number of other neuropathies. Comparable changes have been described in a patient with demyelinating neuropathy in association with type II Waardenberg's syndrome and Hirschsprung's disease (Jacobs and Wilson, 1992), and somewhat less florid findings have been noted in congenital hypomyelinating neuropathies by Vallat and colleagues (Vallat et al., 1987) and in a patient with a heterozygous MPZ point mutation (Nakagawa et al., 1999). It is also observable in transgenic mice, into the genome of which extra copies of the human PMP22 gene have been inserted (personal unpublished observations).
The families with MTMR2 mutations identified so far have originated from Italy, Saudi Arabia, India and England. All had consanguineous parents. The phenotypes reported have been very similar (Gambardella et al., 1997), with all patients affected showing a severe early childhood-onset neuropathy with prominent weakness beginning in the lower limbs, spreading proximally and later affecting the upper limbs. In the Italian and English families, additional features have been weakness of the jaw, facial and bulbar muscles, deafness and diaphragmatic weakness. In our Indian family, the affected individual had a relatively milder clinical and pathological phenotype compared with the other kindreds. These data are provocative and suggest the presence of a significant genotype phenotype effect, the phenotype being dependent upon the severity of the mutation, interaction with SNPs and the resultant available active MTMR2 protein. No clinical data are available as yet from the Saudi Arabian families. Although these cases have been categorized as CMT disease, the phenotype is closer to that of Dejerine–Sottas disease, apart from the fact that the reduction in conduction velocity is less severe than usually accepted for the latter disorder, in which conduction velocities <6–10 m/s are included in the diagnostic characteristics (Dyck et al., 1993; Gabreëls-Festen et al., 1994). This calls into question the utility of these eponymous titles.
The present results characterize further the MTMR2 gene mutations in CMT4B1. They also extend the clinical phenotypes in these families. This was the second gene reported for autosomal recessive HMSN and it appears to account for the majority of autosomal recessive families where the peripheral nerve pathology is characterized by focally folded myelin. The other identified autosomal recessive mutations are those for the early growth response 2 (EGR2) gene (Warner et al., 1998) and the n-myc downstream regulated gene 1 (n-myc DRG1) in HMSN Lom (Kalaydjieva et al., 2000). The rapid progression of the human genome project will enable the cloning of other genes responsible for neuropathies that will permit further genetic classification of this group of disorders.
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Acknowledgments |
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We wish to thank the families in this study for their help. This research was supported by the Wellcome Trust (Grant no. 0056160/2/98/Z).
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Received October 20, 2000. Revised December 14, 2000. Accepted January 5, 2001.
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