Hereditary motor and sensory neuropathy – Lom (HMSNL): refined genetic mapping in Romani (Gypsy) families from several European countries

Chandler, David; Angelicheva, Dora; Heather, L; Gooding, Rebecca; Gresham, David; Yanakiev, Peter; Jonge, Roos de; Baas, Frank; Dye, Danielle E.; Karagyozov, Luchezar; Savov, Aleksey; Blechschmidt, Karin; Keats, Bronya J.B.; Thomas, P K; King, R. H. M.; Starr, Arnold; Nikolova, A.; Colomer, J.; Ishpekova, B.; Tournev, Ivailo; Urtizberea, Jon Andoni; Merlini, Luciano; Butinar, Dusan; Chabrol, B.; Voït, Thomas; Baethmann, Martina; Nedkova, V.; Corches, Axinia; Kalaydjieva, Luba

doi:10.1016/s0960-8966(00)00148-6

Cited by 20 publications

(17 citation statements)

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“…Similar polymorphic haplotypes were subsequently identified in HMSNL chromosomes in affected families across Europe, supporting the assumption of genetic homogeneity and founder effect (Chandler et al 2000). We now report the identification of the HMSNL gene and the founder mutation causing the disease.…”

Section: Introductionsupporting

confidence: 80%

“…The PCR primers for the newly identified markers were those described by Chandler et al (2000). Vertical-gel electrophoresis, which was performed in a Hoeffer Pokerface II apparatus, was followed by autoradiography for 2-12 h. Allele calling was performed manually.…”

Section: Refined Genetic Mappingmentioning

confidence: 99%

“…Refined genetic mapping included 174 individuals (60 patients and 114 unaffected relatives) from seven European countries; the individuals were genotyped for 24 polymorphic microsatellites, 19 of which were identified in our study (Chandler et al 2000). Ten recombinant haplotypes, whose distribution differed between disease chromosomes originating from the diverse Romani groups, helped to narrow the HMSNL region ( fig.…”

Section: Physical and Refined Genetic Mappingmentioning

confidence: 99%

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N‐MYC Downstream‐Regulated Gene 1 Is Mutated In Hereditary Motor And Sensory Neuropathy‐LOM

Kalaydjieva¹,

Gresham²,

Gooding³

et al. 2001

J Peripheral Nervous Sys

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Citation for published version (APA):Kalaydjieva, L., Gresham, D., Gooding, R., Heather, L., Baas, F., de Jonge, R., ... Thomas, P. K. (2000). N-myc downstream-regulated gene 1 is mutated in hereditary motor and sensory neuropathy-Lom. American Journal of Human Genetics, 67, 47-58. General rightsIt is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons). Disclaimer/Complaints regulationsIf you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: http://uba.uva.nl/en/contact, or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible. Download date: 11 May 2018Am. J. Hum. Genet. 67:47-58, 2000 47 Hereditary motor and sensory neuropathies, to which Charcot-Marie-Tooth (CMT) disease belongs, are a common cause of disability in adulthood. Growing awareness that axonal loss, rather than demyelination per se, is responsible for the neurological deficit in demyelinating CMT disease has focused research on the mechanisms of early development, cell differentiation, and cell-cell interactions in the peripheral nervous system. Autosomal recessive peripheral neuropathies are relatively rare but are clinically more severe than autosomal dominant forms of CMT, and understanding their molecular basis may provide a new perspective on these mechanisms. Here we report the identification of the gene responsible for hereditary motor and sensory neuropathy-Lom (HMSNL). HMSNL shows features of Schwann-cell dysfunction and a concomitant early axonal involvement, suggesting that impaired axonglia interactions play a major role in its pathogenesis. The gene was previously mapped to 8q24.3, where conserved disease haplotypes suggested genetic homogeneity and a single founder mutation. We have reduced the HMSNL interval to 200 kb and have characterized it by means of large-scale genomic sequencing. Sequence analysis of two genes located in the critical region identified the founder HMSNL mutation: a premature-termination codon at position 148 of the N-myc downstream-regulated gene 1 (NDRG1). NDRG1 is ubiquitously expressed and has been proposed to play a role in growth arrest and cell differentiation, possibly as a signaling protein shuttling between the cytoplasm and the nucleus. We have studied expression in peripheral nerve and have detected particularly high levels in the Schwann cell. Taken together, these findings point to NDRG1 having a role in the peripheral nervous system, possibly in the Schwann-cell signaling necessary for axonal survival. N-myc Downstream-Regulated Gene 1 Is Muta...

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Section: Introductionsupporting

confidence: 80%

Section: Refined Genetic Mappingmentioning

confidence: 99%

Section: Physical and Refined Genetic Mappingmentioning

confidence: 99%

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N‐MYC Downstream‐Regulated Gene 1 Is Mutated In Hereditary Motor And Sensory Neuropathy‐LOM

Kalaydjieva¹,

Gresham²,

Gooding³

et al. 2001

J Peripheral Nervous Sys

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“…These neuropathological features suggest that impairment of SC-axonal interaction is a major component of the pathogenesis of HMSNL. The disease occurs exclusively among the Roma (Gypsies), with related polymorphic haplotypes pointing to a single founder mutation shared by affected individuals across Europe [Kalaydjieva et al, 1996;Chandler et al, 2000]. The founder mutation was found to be a C4T transition in exon 7, at mRNA nucleotide position 552 (GenBank: XM _ 005243), resulting in the replacement of arginine by a translation termination signal at codon position 148 (R148X) .…”

Section: Introductionmentioning

confidence: 99%

Mutation screening of the N-myc downstream-regulated gene 1 (NDRG1) in patients with Charcot-Marie-Tooth Disease

Hunter¹,

Bernard²,

Freitas³

et al. 2003

Hum. Mutat.

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In a previous study, we have shown that N-myc downstream-regulated gene 1 (NDRG1), classified in databases as a tumor suppressor and heavy metal-response protein, is mutated in hereditary motor and sensory neuropathy Lom (HMSNL), a severe autosomal recessive form of Charcot-Marie-Tooth (CMT) disease. The private founder mutation R148X, causing HMSNL in patients of Romani ethnicity, has so far remained the only molecular defect linking NDRG1 to a specific disease phenotype. Here we report the first study aiming to assess the overall contribution of this gene to the pathogenesis of peripheral neuropathies, in cases where the most common causes of CMT disease have been excluded. Sequence analysis of NDRG1 in 104 CMT patients of diverse ethnicity identified one novel disease-causing mutation, IVS8-1G>A (g.2290787G>A), which affects the splice-acceptor site of IVS8 and results in the skipping of exon 9. The phenotype of the IVS8-1G>A homozygote was very closely related to that of HMSNL patients. In addition, we have detected homozygosity for the known R148X mutation in two affected individuals. Mutations in NDRG1 thus accounted for 2.88% of our overall group of patients, and for 4.68% of cases with demyelinating neuropathies. No other variants were identified in the coding sequence, whereas 12 single nucleotide polymorphisms were observed in the introns. Hum Mutat 22:129-135, 2003.

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“…Within the Roma gypsies -as frequently occurs in culturally isolated communities -consanguinity between spouses is almost the rule and, as a consequence, genetically based diseases are often found. The more common diseases affecting, either directly or indirectly, the nervous system include heredodegenerative neuropathy, muscular dystrophy and coagulation disorders [7][8][9] . To date, this is the first report documenting the occurrence of moyamoya disease in the Roma gypsy ethnicity.…”

Section: Discussionmentioning

confidence: 99%

Moyamoya Disease in a Member of the Roma Gypsy Community

et al. 2008

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Hereditary motor and sensory neuropathy – Lom (HMSNL): refined genetic mapping in Romani (Gypsy) families from several European countries

Cited by 20 publications

References 16 publications

N‐MYC Downstream‐Regulated Gene 1 Is Mutated In Hereditary Motor And Sensory Neuropathy‐LOM

N‐MYC Downstream‐Regulated Gene 1 Is Mutated In Hereditary Motor And Sensory Neuropathy‐LOM

Mutation screening of the N-myc downstream-regulated gene 1 (NDRG1) in patients with Charcot-Marie-Tooth Disease

Moyamoya Disease in a Member of the Roma Gypsy Community

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