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Human Molecular Genetics Pages 1685-1688
Homozygosity mapping of an autosomal recessive form of demyelinating Charcot-Marie-Tooth disease to chromosome 5q23-q33
Introduction
Results
Discussion
Materials And Methods
   Families
   Genotyping
   Linkage analysis
References

Homozygosity mapping of an autosomal recessive form of demyelinating Charcot-Marie-Tooth disease to chromosome 5q23-q33

Homozygosity mapping of an autosomal recessive form of demyelinating Charcot-Marie-Tooth disease to chromosome 5q23-q33 E. LeGuern1,2,+,*, A. Guilbot1,+, M. Kessali4, N. Ravisé1, J. Tassin1, T. Maisonobe3, D. Grid4 and A. Brice1,2

1INSERM U289, 2Fédération de Neurologie, 3Laboratoire de Neuropathologie R. Escourolle, Hôpital de la Salpêtrière, Paris, France and 4Service de Neurologie, CHU Mustapha, Algiers, Algeria

Received June 12, 1996; Revised and Accepted July 18, 1996

Charcot-Marie-Tooth (CMT) disease is the most frequent inherited peripheral motor and sensory neuropathy characterised by chronic distal weakness with progressive muscular atrophy and sensory loss of the distal extremities. The dominant form of the disease is genetically heterogeneous but only one locus has been identified on chromosome 8q13-q21.1 for autosomal recessive CMT. By homozygosity mapping in a large Algerian kindred, we have assigned a second locus for autosomal recessive CMT to chromosome 5q23-33. Linkage analysis demonstrated that the same locus is involved in a second Algerian family with a demyelinating CMT. Haplotype reconstruction and determination of the minimal region of homozygosity restricts the candidate region to a 4 cM interval.

INTRODUCTION

Charcot-Marie-Tooth (CMT) disease is the most frequent inherited peripheral motor and sensory neuropathy. The disease is characterised by chronic distal weakness with progressive muscular atrophy and sensory loss in the distal extremities (1 ). Classification is now based on the responsible loci in addition to the classical electrophysiological criteria, in particular median nerve conduction velocity and mode of inheritance: autosomal dominant (CMT1A, CMT1B, CMT2A, CMT2B) (2 -5 ),recessive or dominant X-linked (6 ) and autosomal recessive (CMT4). The first locus for an autosomal recessive form of demyelinating CMT, designated CMT4A, was determined in four Tunisian families by Ben Othmane et al. (7 ,8 ),in 8q13-21.1. The patients presented decreased motor nerve conduction velocities. Loss of large myelinated fibers with hypomyelination and basal lamina onion bulbs were observed on nerve biopsy. No evidence of genetic heterogeneity was found among the four families tested.

In the present study, we have assigned the second locus for the autosomal recessive form of demyelinating CMT to chromosome 5q23-q33, by homozygosity mapping, in a large Algerian family with consanguinity. Linkage analysis revealed that this locus is also involved in another Algerian pedigree. Haplotype reconstruction and determination of the region of homozygosity localized the corresponding gene within a 4 cM interval.

RESULTS

After exclusion of three loci responsible for demyelinating CMT, CMT1A on 17p, CMT1B on 1q and CMT4A on 8q, in the families ALG-BOU and ALG-ABD (data not shown), a genome-wide search was performed in the former (Fig. 1 ). Fifty two polymorphic microsatellite markers (positional odds >1000:1 and minimal heterozygosity of 0.65), selected from the Généthon map (9 ), excluded ~25% of the autosomes.


Figure 1.Haplotype reconstruction in families ALG-BOU and ALG-ABD for 5q markers. Affected and unaffected individuals are represented by black and open symbols, respectively. Disease-bearing chromosomes are boxed and hatched areas represent the regions of homozygosity in each family. Deduced haplotypes for individual 1 in family ALG-ABD were bracketed. Position of recombination events are indicated by an arrow.

The eight affected siblings were homozygous for the markers D5S643 and D5S436, which are closely linked on the Généthon map, suggesting linkage between the disease and these two markers. Linkage was confirmed by two point linkage analysis with Zmax = 2.53 at [theta] = 0.00 for both markers (Table 1 ). As each parent was homozygous for one of these two microsatellites, the haplotype for the linked markers D5S643 and D5S436 was considered as a single locus in linkage analysis. A significant lod score of 4.81 at [theta] = 0.00 was generated. Sixteen additional microsatellite markers covering 33 cM on chromosome 5q, were tested (Table 1 ). Positive lod scores were obtained for most of them, reaching a peak value of Zmax = 3.42 at [theta] = 0.05 for D5S636 and D5S410. The more conservative `affected only' method yielded similar pairwise lod scores with maximal values of 3.30 for both markers D5S636 and D5S410.


Table 1 . Results of two-point lod scores for eight markers on chromosome 5q in families ALG-BOU and ALG-ABD


An additional family, ALG-ABD, with the same phenotype was tested for 14 of the 5q markers (Table 1 ). All patients were homozygous for five markers located in an interval overlapping the region of homozygosity determined in family ALG-BOU. A maximal positive lod score of Zmax = 2.09 at [theta] = 0.00 was obtained for both markers D5S393 and D5S436. These data demonstrated that the same locus was also responsible for the disease in family ALG-ABD. The combined results of both families generated a peak lod score of 4.62 at [theta] = 0.00 for D5S436.

Haplotype reconstruction and analysis of the recombination events between markers and the disease locus in affected individuals 14, 15, 16 and 17 in family ALG-BOU and 7 in family ALG-ABD, demonstrated that the gene was localized in the 13 cM region flanked by the markers D5S658 and D5S670. Homozygosity in patients was observed at two linked loci in family ALG-BOU and five in family ALG-ABD. The minimal overlapping region of homozygosity for both families restricted the locus to the 4 cM interval between D5S658 and the markers D5S402 and D5S638 which map to the same position (Fig. 2 ).

DISCUSSION

By homozygosity mapping, we have assigned to chromosome 5q23-33 the locus for an autosomal recessive form of demyelinating CMT in two Algerian families with consanguinity. Significant lod scores above the threshold of 3, were obtained in family ALG-BOU with markers D5S410 and D5S636 and by combined analysis with the closely linked markers D5S436 and D5S643. In family ALG-ABD, with a similar phenotype, positive lod scores, reaching 2.09 for markers D5S393 and D5S436 were generated, highly supporting the hypothesis of linkage with the same locus. Haplotype reconstruction detected recombination events which localized the gene within a 13 cM region between D5S658 and D5S670, and characterized the minimal overlapping region of homozygosity, which reduced the candidate interval to a 4 cM region flanked by D5S658 and the colocalized markers D5S402 and D5S638. Although both families came from the same region of Algeria, the haplotypes segregating with the disorder were different, suggesting the existence of different founders. However, the hypothesis of a common ancestral mutation for both families with haplotype divergence by recombination events cannot be excluded.

Since a 4 cM interval may represent a physical region of 4 Mb, analysis of additional families and markers is needed to reduce the candidate interval before initiating positional cloning. With the four highly informative microsatellite markers in the 4 cM candidate region, linkage at the 5q23-33 locus can be tested even in relatively small pedigrees with recessive CMT. Several genes have been indentified in the 5q23-33 region, but none of them appears to be an evident candidate for demyelinating CMT, either from its function or its pattern of expression. In particular, no genes coding for peripheral myelin proteins mapped to this region. Mouse chromosome 18 presents a region homologous to human chromosome 5q23-33, but no murine disease similar to CMT have been yet described and mapped to chromosome 18.


Figure 2.Regional genetic map of chromosome 5q. Eighteen markers with positional odds 1000:1, used for linkage analysis are indicated with their respective recombination rates (9). Location of recombination events are indicated by an horizontal arrow with the number of the corresponding patient. The regions of homozygosity for families ALG-BOU and ALG-ABD are represented by solid and hatched vertical lines, respectively.


The clinical, electrophysiological and neuropathological heterogeneity of autosomal recessive CMT (ARCMT) has been known for years (10 -13 ). This is the first demonstration of genetic heterogeneity for the demyelinating form of ARCMT. The first locus was mapped to chromosome 8q in four Tunisian families. The two Algerian kindreds associated with the locus on chromosome 5q23-33, are characterized by a sensory-motor neuropathy with onset in childhood or adolescence, frequently associated with pes cavus and scoliosis, and a mild walking disability after a 15 year disease duration. There is a discrepancy between the rapid worsening of deformities and the relatively slow progression of the motor deficit. Cutaneous sensation is most frequently impaired first, followed by vibration sense and joint position sensory loss. Electrophysiology reveals decreased nerve conduction velocities (NCV) with median motor NCV ranging between 20 and 32 m/s and decreased or absent sensory nerve action potentials. Finally, thin myelin sheaths and onion bulb formations are present in sural nerve biopsies (Kessali et al., in preparation). These clinical, electrophysiological and neuropathological features are very similar to those described for the autosomal dominant form of CMT1. However, the precocity and rapid progression of deformities are specific features of this form of ARCMT.

MATERIALS AND METHODS

Families

Two consanguineous Algerian families were examined in the department of Neurology of the Mustapha Hospital in Algiers, Algeria. Electrophysiological studies were performed on 18 families members, including 12 affected individuals. Individuals were considered as affected using the following criteria: presence of signs of motor and sensory neuropathy, at least in the lower limbs, and median nerve conduction velocity <40 m/s. Mean median NCV in affected individuals was 24 +- 5.1 m/s, reflecting a demyelinating process.

Genotyping

Blood samples were taken from 18 consenting individuals, and high molecular weight genomic DNA was extracted. Two hundred dinucleotide CA repeats from the Généthon map were selected for the genome search. Genotyping of dinucleotide repeats was performed using standard procedures (14 ).

Linkage analysis

Pairwise lod-scores were calculated using the MLINK program (15 ) of the FASTLINK package (16 ). Lod scores were calculated under the assumption of equal allele frequencies. Recombination fractions were assumed to be equal for males and females and were converted to map distances using the Haldane mapping function. Disease was considered autosomal recessive with a gene frequency of 10-4.

REFERENCES

1 Dyck, P.J., Chance, P., Lebo, R. and Carney, J.A. (1993) In Dyck, P.J., Thomas, P.K., Griffin, J.W., Low, P.A. and Poduslo, J.F. (eds) Hereditary, Motor and Sensory Neuropathies. Philadelphia, W.B., Saunders, 1094-1136.

2 Rayemaekers, P., Timmerman, V., Nelis, E., De Jonghe, P., Hoogendijk, J.E., Baas, F., Barker, D.F., Martin, J.J., De Visser, M., Bolhuis, P.A., Van Broeckhoven, C. and the HSMN collaborative research group. (1991) Duplication in chromosome 17p 11.2 in Charcot-Marie-Tooth neuropathy type 1a (CMT1a). Neuromusc. Dis. 1, 93-97.

3 Lupski, J.R., Montes de Oca-Luna, R., Slaugenhaupt, S., Pentao, L., Guzzetta, V., Trask, B.J., Saucedo-Cardenas, O., Barker, D.F., Killian, J.M., Garcia, C.A., Chakravarti, A. and Patel, P.I. (1991) DNA duplication associated with Charcot-Marie-Tooth disease type 1A. Cell 66, 219-232. MEDLINE Abstract

4 Ben Othmane, K., Middleton, L.,T., Loprest, L.J., Wilkinson, K.M., Lennon, F., Rozear, M.P., Tajich, J.M., Gaskell, P.C., Roses, A.D., Pericak-Vance, M.A. and Vance, J. (1993) Localization of a gene (CMT2A) for autosomal dominant Charcot-Marie-Tooth disease type 2 to chromosome 1p and evidence of genetic heterogeneity. Genomics 17, 370-375. MEDLINE Abstract

5 Kwon, J.M., Elliott, J.L., Yee, W.Y., Ivanovich, J., Scavarda, N.J., Moolsinton, P.J. and Goodfellow, P.J. (1995) Assignment of a second Charcot-Marie-Tooth type II locus to chromosome 3q. Am. J. Hum. Genet. 57, 853-858. MEDLINE Abstract

6 Bergoffen, J.A., Trofatter, J., Pericak-Vance, M.A., Haines, J.L., Chance, P.F. and Fischbeck, K.H. (1993) Linkage localization of X-linked Charcot-Marie-Tooth disease. Am. J. Hum. Genet. 52, 312-318.

7 Ben Othmane, K.B., Hentati, F., Lennon, F., Ben Hamida, C., Bled, S., Roses, A.D., Pericak-Vance, M.A., Ben Hamida, M. and Vance, J.M. (1993) Linkage of a locus (CMT4A) for autosomal recessive Charcot-Marie-Tooth disease to chromosome 8q. Hum. Mol. Genet. 2, 1625-1628. MEDLINE Abstract

8 Ben Othmane, K.B., Loeb, D., Hayworth-Hodgte, R., Hentati, F., Rao, N., Roses, A.D., Ben Hamida, M., Pericak-Vance, M.A. and Vance, J.M. (1995) Physical and genetic mapping of the CMT4 A locus and exclusion of PMP-2 as the defect in CMT4A. Genomics 28, 286-290.

9 Gyapay, G., Morissette, J., Vignal, A., Dib, C., Fizames, C., Millaseau, P., Marc, S., Bemardi, G., Lathrop, M. and Weissenbach, J. (1994) The 1993-1994 Généthon human genetic linkage map. Nature Genet. 7, 246-339. MEDLINE Abstract

10 Bouldin, T.W., Riley, E., Hall, C.D. and Swift, M. (1980) Clinical and pathological features of an autosomal recessive neuropathy. J. Neurol. Sci. 46, 315-323.

11 Ouvrier, R.A, Mc.Leod ,T.E. and Conchin, (1987) The hypertrophic forms of hereditary motor and sensory neuropathy. Brain 110, 121-148. MEDLINE Abstract

12 Gabreëls-Felsten, A.A.W.M., Gabreëls, F.J.M., Jennekens, F.G.I., Joosten, E.M.G. and Janssen-van Kempen, T.W. (1992) Autosomal recessive form of hereditary motor and sensory neuropathy type I. Neurology 42, 1755-1761. MEDLINE Abstract

13 Harding, A.E. and Thomas, P.K. (1980) Autosomal recessive forms of hereditary motor and sensory neuropathy. J. Neurol. Neurosurg. Psychiatry 43, 669-678. MEDLINE Abstract

14 Stevanin, G., Le Guern, E., Ravise, N., Chneiweiss, H., Dürr, A., Cancel, G., Vignal, A., Boch, A.L., Ruberg, M., Penet, C. et al. (1994) A third locus for autosomal dominant cerebellar ataxia type I maps to chromosome 14q 24.3-qter. Evidence for the existence of a fourth locus. Am. J. Hum. Genet. 54, 11-20. MEDLINE Abstract

15 Lathrop, G., Lalouel, J., Julier, C. and Ott, J. (1985) Multilocus linkage analysis in humans: detection of linkage and estimation of recombination. Am. J. Hum. Genet. 37, 482-498. MEDLINE Abstract

16 Schäffer, A.A., Gupta, S.K. and Cottingham, R.W., Jr (1994) Avoiding recomputation in genetic linkage analysis. Hum. Hered. 44, 225-237. MEDLINE Abstract

*To whom correspondence should be addressed at: INSERM U289, Hôpital de la Salpêtrière, 47 Bd de l'Hôpital, 75651 Paris cedex 13, France+Both authors contributed equally to this work

This page is maintained by OUP admin. Last updated Thu Oct 31 15:27:49 GMT 1996. Part of the OUP Journals World Wide Web service.Copyright Oxford University Press, 1996


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