TY - JOUR
T1 - Nerve conduction velocity is regulated by the inositol polyphosphate-4- phosphatase II gene
AU - Lemcke, Susanne
AU - Müller, Susen
AU - Möller, Steffen
AU - Schillert, Arne
AU - Ziegler, Andreas
AU - Cepok-Kauffeld, Sabine
AU - Comabella, Manuel
AU - Montalban, Xavier
AU - Rülicke, Thomas
AU - Nandakumar, Kutty Selva
AU - Hemmer, Bernhard
AU - Holmdahl, Rikard
AU - Pahnke, Jens
AU - Ibrahim, Saleh M.
N1 - Funding Information:
Supported by German Research Foundation grant EXC 306/1 (S.M.I.) and by funding from the European Community’s Framework programs under grant agreements Neurinox ( Health-F2-2011-278611 ) and Masterswitch ( HEALTH-F2-2008-223404 ) (R.H.).
PY - 2014/9
Y1 - 2014/9
N2 - Impairment of nerve conduction is common in neurodegenerative and neuroinflammatory diseases such as multiple sclerosis (MS), and measurement of evoked potentials (visual, motor, or sensory) has been widely used for diagnosis and recently also as a prognostic marker for MS. We used a classical genetic approach to identify novel genes controlling nerve conduction. First, we used quantitative trait mapping in F2 progeny of B10/SJL mice to identify EAE31, a locus controlling latency of motor evoked potentials (MEPs) and clinical onset of experimental autoimmune encephalomyelitis. Then, by combining congenic mapping, in silico haplotype analyses, and comparative genomics we identified inositol polyphosphate-4-phosphatase, type II (Inpp4b) as the quantitative trait gene for EAE31. Sequence variants of Inpp4b (C/A, exon 13; A/C, exon 14) were identified as differing among multiple mouse strains and correlated with individual cortical MEP latency differences. To evaluate the functional relevance of the amino acid exchanges at positions S474R and H548P, we generated transgenic mice carrying the longer-latency allele (Inpp4b 474R/548P) in the C57BL/6J background. Inpp4b474R/548P mice exhibited significantly longer cortical MEP latencies (4.5 ± 0.22 ms versus 3.7 ± 0.13 ms; P = 1.04 × 10-9), indicating that INPP4B regulates nerve conduction velocity. An association of an INPP4B polymorphism (rs13102150) with MS was observed in German and Spanish MS cohorts (3676 controls and 911 cases) (P = 8.8 × 10-3).
AB - Impairment of nerve conduction is common in neurodegenerative and neuroinflammatory diseases such as multiple sclerosis (MS), and measurement of evoked potentials (visual, motor, or sensory) has been widely used for diagnosis and recently also as a prognostic marker for MS. We used a classical genetic approach to identify novel genes controlling nerve conduction. First, we used quantitative trait mapping in F2 progeny of B10/SJL mice to identify EAE31, a locus controlling latency of motor evoked potentials (MEPs) and clinical onset of experimental autoimmune encephalomyelitis. Then, by combining congenic mapping, in silico haplotype analyses, and comparative genomics we identified inositol polyphosphate-4-phosphatase, type II (Inpp4b) as the quantitative trait gene for EAE31. Sequence variants of Inpp4b (C/A, exon 13; A/C, exon 14) were identified as differing among multiple mouse strains and correlated with individual cortical MEP latency differences. To evaluate the functional relevance of the amino acid exchanges at positions S474R and H548P, we generated transgenic mice carrying the longer-latency allele (Inpp4b 474R/548P) in the C57BL/6J background. Inpp4b474R/548P mice exhibited significantly longer cortical MEP latencies (4.5 ± 0.22 ms versus 3.7 ± 0.13 ms; P = 1.04 × 10-9), indicating that INPP4B regulates nerve conduction velocity. An association of an INPP4B polymorphism (rs13102150) with MS was observed in German and Spanish MS cohorts (3676 controls and 911 cases) (P = 8.8 × 10-3).
UR - http://www.scopus.com/inward/record.url?scp=84906320748&partnerID=8YFLogxK
U2 - 10.1016/j.ajpath.2014.05.021
DO - 10.1016/j.ajpath.2014.05.021
M3 - Article
C2 - 25129256
AN - SCOPUS:84906320748
SN - 0002-9440
VL - 184
SP - 2420
EP - 2429
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 9
ER -