A Gly98Val mutation in the N-myc downstream regulated gene 1 (NDRG1) in Alaskan Malamutes with polyneuropathy

Camilla Vibeke Sichlau Bruun; Karin H. Jäderlund; Mette Berendt; Kristine Bastholm Jensen; Eva-Maria Hohneck Spodsberg; Hanne Birgit Gredal; G. Diane Shelton; James R. Mickelson; Katie M. Minor; Hannes Lohi; Inge Bjerkås; Øyvind Stigen; Arild Espenes; Cecilia Rohdin; Rebecca Edlund; Jennie Ohlsson; Sigitas Cizinauskas; Páll S. Leifsson; Cord Drögemüller; Lars Moe; Susanna Cirera Salicio; Merete Fredholm

doi:10.1371/journal.pone.0054547

A Gly98Val mutation in the N-myc downstream regulated gene 1 (NDRG1) in Alaskan Malamutes with polyneuropathy

Camilla Vibeke Sichlau Bruun, Karin H. Jäderlund, Mette Berendt, Kristine Bastholm Jensen, Eva-Maria Hohneck Spodsberg, Hanne Birgit Gredal, G. Diane Shelton, James R. Mickelson, Katie M. Minor, Hannes Lohi, Inge Bjerkås, Øyvind Stigen, Arild Espenes, Cecilia Rohdin, Rebecca Edlund, Jennie Ohlsson, Sigitas Cizinauskas, Páll S. Leifsson, Cord Drögemüller, Lars MoeSusanna Cirera Salicio, Merete Fredholm

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Abstract

The first cases of early-onset progressive polyneuropathy appeared in the Alaskan Malamute population in Norway in the late 1970s. Affected dogs were of both sexes and were ambulatory paraparetic, progressing to non-ambulatory tetraparesis. On neurologic examination, affected dogs displayed predominantly laryngeal paresis, decreased postural reactions, decreased spinal reflexes and muscle atrophy. The disease was considered eradicated through breeding programmes but recently new cases have occurred in the Nordic countries and the USA. The N-myc downstream-regulated gene (NDRG1) is implicated in neuropathies with comparable symptoms or clinical signs both in humans and in Greyhound dogs. This gene was therefore considered a candidate gene for the polyneuropathy in Alaskan Malamutes. The coding sequence of the NDRG1 gene derived from one healthy and one affected Alaskan Malamute revealed a non-synonymous G>T mutation in exon 4 in the affected dog that causes a Gly98Val amino acid substitution. This substitution was categorized to be "probably damaging" to the protein function by PolyPhen2 (score: 1.000). Subsequently, 102 Alaskan Malamutes from the Nordic countries and the USA known to be either affected (n = 22), obligate carriers (n = 7) or healthy (n = 73) were genotyped for the SNP using TaqMan. All affected dogs had the T/T genotype, the obligate carriers had the G/T genotype and the healthy dogs had the G/G genotype except for 13 who had the G/T genotype. A protein alignment showed that residue 98 is conserved in mammals and also that the entire NDRG1 protein is highly conserved (94.7%) in mammals. We conclude that the G>T substitution is most likely the mutation that causes polyneuropathy in Alaskan Malamutes. Our characterization of a novel candidate causative mutation for polyneuropathy offers a new canine model that can provide further insight into pathobiology and therapy of human polyneuropathy. Furthermore, selection against this mutation can now be used to eliminate the disease in Alaskan Malamutes.

Original language	English
Article number	e54547
Journal	PLOS one
Volume	8
Issue number	2
Pages (from-to)	1-7
Number of pages	7
ISSN	1932-6203
DOIs	https://doi.org/10.1371/journal.pone.0054547
Publication status	Published - 5 Feb 2013

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Bruun, C. V. S., Jäderlund, K. H., Berendt, M., Jensen, K. B., Spodsberg, E.-M. H., Gredal, H. B., Shelton, G. D., Mickelson, J. R., Minor, K. M., Lohi, H., Bjerkås, I., Stigen, Ø., Espenes, A., Rohdin, C., Edlund, R., Ohlsson, J., Cizinauskas, S., Leifsson, P. S., Drögemüller, C., ... Fredholm, M. (2013). A Gly98Val mutation in the N-myc downstream regulated gene 1 (NDRG1) in Alaskan Malamutes with polyneuropathy. PLOS one, 8(2), 1-7. Article e54547. https://doi.org/10.1371/journal.pone.0054547

Bruun, CVS, Jäderlund, KH, Berendt, M, Jensen, KB, Spodsberg, E-MH , Gredal, HB, Shelton, GD, Mickelson, JR, Minor, KM, Lohi, H, Bjerkås, I, Stigen, Ø, Espenes, A, Rohdin, C, Edlund, R, Ohlsson, J, Cizinauskas, S, Leifsson, PS, Drögemüller, C, Moe, L, Cirera Salicio, S & Fredholm, M 2013, 'A Gly98Val mutation in the N-myc downstream regulated gene 1 (NDRG1) in Alaskan Malamutes with polyneuropathy', PLOS one, vol. 8, no. 2, e54547, pp. 1-7. https://doi.org/10.1371/journal.pone.0054547

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title = "A Gly98Val mutation in the N-myc downstream regulated gene 1 (NDRG1) in Alaskan Malamutes with polyneuropathy",

abstract = "The first cases of early-onset progressive polyneuropathy appeared in the Alaskan Malamute population in Norway in the late 1970s. Affected dogs were of both sexes and were ambulatory paraparetic, progressing to non-ambulatory tetraparesis. On neurologic examination, affected dogs displayed predominantly laryngeal paresis, decreased postural reactions, decreased spinal reflexes and muscle atrophy. The disease was considered eradicated through breeding programmes but recently new cases have occurred in the Nordic countries and the USA. The N-myc downstream-regulated gene (NDRG1) is implicated in neuropathies with comparable symptoms or clinical signs both in humans and in Greyhound dogs. This gene was therefore considered a candidate gene for the polyneuropathy in Alaskan Malamutes. The coding sequence of the NDRG1 gene derived from one healthy and one affected Alaskan Malamute revealed a non-synonymous G>T mutation in exon 4 in the affected dog that causes a Gly98Val amino acid substitution. This substitution was categorized to be {"}probably damaging{"} to the protein function by PolyPhen2 (score: 1.000). Subsequently, 102 Alaskan Malamutes from the Nordic countries and the USA known to be either affected (n = 22), obligate carriers (n = 7) or healthy (n = 73) were genotyped for the SNP using TaqMan. All affected dogs had the T/T genotype, the obligate carriers had the G/T genotype and the healthy dogs had the G/G genotype except for 13 who had the G/T genotype. A protein alignment showed that residue 98 is conserved in mammals and also that the entire NDRG1 protein is highly conserved (94.7%) in mammals. We conclude that the G>T substitution is most likely the mutation that causes polyneuropathy in Alaskan Malamutes. Our characterization of a novel candidate causative mutation for polyneuropathy offers a new canine model that can provide further insight into pathobiology and therapy of human polyneuropathy. Furthermore, selection against this mutation can now be used to eliminate the disease in Alaskan Malamutes.",

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T1 - A Gly98Val mutation in the N-myc downstream regulated gene 1 (NDRG1) in Alaskan Malamutes with polyneuropathy

AU - Bruun, Camilla Vibeke Sichlau

AU - Jäderlund, Karin H.

AU - Berendt, Mette

AU - Jensen, Kristine Bastholm

AU - Spodsberg, Eva-Maria Hohneck

AU - Gredal, Hanne Birgit

AU - Shelton, G. Diane

AU - Mickelson, James R.

AU - Minor, Katie M.

AU - Lohi, Hannes

AU - Bjerkås, Inge

AU - Stigen, Øyvind

AU - Espenes, Arild

AU - Rohdin, Cecilia

AU - Edlund, Rebecca

AU - Ohlsson, Jennie

AU - Cizinauskas, Sigitas

AU - Leifsson, Páll S.

AU - Drögemüller, Cord

AU - Moe, Lars

AU - Cirera Salicio, Susanna

AU - Fredholm, Merete

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N2 - The first cases of early-onset progressive polyneuropathy appeared in the Alaskan Malamute population in Norway in the late 1970s. Affected dogs were of both sexes and were ambulatory paraparetic, progressing to non-ambulatory tetraparesis. On neurologic examination, affected dogs displayed predominantly laryngeal paresis, decreased postural reactions, decreased spinal reflexes and muscle atrophy. The disease was considered eradicated through breeding programmes but recently new cases have occurred in the Nordic countries and the USA. The N-myc downstream-regulated gene (NDRG1) is implicated in neuropathies with comparable symptoms or clinical signs both in humans and in Greyhound dogs. This gene was therefore considered a candidate gene for the polyneuropathy in Alaskan Malamutes. The coding sequence of the NDRG1 gene derived from one healthy and one affected Alaskan Malamute revealed a non-synonymous G>T mutation in exon 4 in the affected dog that causes a Gly98Val amino acid substitution. This substitution was categorized to be "probably damaging" to the protein function by PolyPhen2 (score: 1.000). Subsequently, 102 Alaskan Malamutes from the Nordic countries and the USA known to be either affected (n = 22), obligate carriers (n = 7) or healthy (n = 73) were genotyped for the SNP using TaqMan. All affected dogs had the T/T genotype, the obligate carriers had the G/T genotype and the healthy dogs had the G/G genotype except for 13 who had the G/T genotype. A protein alignment showed that residue 98 is conserved in mammals and also that the entire NDRG1 protein is highly conserved (94.7%) in mammals. We conclude that the G>T substitution is most likely the mutation that causes polyneuropathy in Alaskan Malamutes. Our characterization of a novel candidate causative mutation for polyneuropathy offers a new canine model that can provide further insight into pathobiology and therapy of human polyneuropathy. Furthermore, selection against this mutation can now be used to eliminate the disease in Alaskan Malamutes.

AB - The first cases of early-onset progressive polyneuropathy appeared in the Alaskan Malamute population in Norway in the late 1970s. Affected dogs were of both sexes and were ambulatory paraparetic, progressing to non-ambulatory tetraparesis. On neurologic examination, affected dogs displayed predominantly laryngeal paresis, decreased postural reactions, decreased spinal reflexes and muscle atrophy. The disease was considered eradicated through breeding programmes but recently new cases have occurred in the Nordic countries and the USA. The N-myc downstream-regulated gene (NDRG1) is implicated in neuropathies with comparable symptoms or clinical signs both in humans and in Greyhound dogs. This gene was therefore considered a candidate gene for the polyneuropathy in Alaskan Malamutes. The coding sequence of the NDRG1 gene derived from one healthy and one affected Alaskan Malamute revealed a non-synonymous G>T mutation in exon 4 in the affected dog that causes a Gly98Val amino acid substitution. This substitution was categorized to be "probably damaging" to the protein function by PolyPhen2 (score: 1.000). Subsequently, 102 Alaskan Malamutes from the Nordic countries and the USA known to be either affected (n = 22), obligate carriers (n = 7) or healthy (n = 73) were genotyped for the SNP using TaqMan. All affected dogs had the T/T genotype, the obligate carriers had the G/T genotype and the healthy dogs had the G/G genotype except for 13 who had the G/T genotype. A protein alignment showed that residue 98 is conserved in mammals and also that the entire NDRG1 protein is highly conserved (94.7%) in mammals. We conclude that the G>T substitution is most likely the mutation that causes polyneuropathy in Alaskan Malamutes. Our characterization of a novel candidate causative mutation for polyneuropathy offers a new canine model that can provide further insight into pathobiology and therapy of human polyneuropathy. Furthermore, selection against this mutation can now be used to eliminate the disease in Alaskan Malamutes.

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DO - 10.1371/journal.pone.0054547

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SN - 1932-6203

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ER -

A Gly98Val mutation in the N-myc downstream regulated gene 1 (NDRG1) in Alaskan Malamutes with polyneuropathy

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