An SCN9A channelopathy causes congenital inability to experience pain

被引:1136
作者
Cox, James J.
Reimann, Frank
Nicholas, Adeline K.
Thornton, Gemma
Roberts, Emma
Springell, Kelly
Karbani, Gulshan
Jafri, Hussain
Mannan, Jovaria
Raashid, Yasmin
Al-Gazali, Lihadh
Hamamy, Henan
Valente, Enza Maria
Gorman, Shaun
Williams, Richard
McHale, Duncan P.
Wood, John N.
Gribble, Fiona M.
Woods, C. Geoffrey
机构
[1] Addenbrookes Hosp, Dept Med Genet, Cambridge CB2 OXY, England
[2] Addenbrookes Hosp, Cambridge Inst Med Res, Dept Clin Biochem, Cambridge CB2 OXY, England
[3] St James Univ Hosp, Sect Ophthalmol & Neurosci, Leeds Inst Mol Med, Leeds LS9 7TF, W Yorkshire, England
[4] St James Univ Hosp, Dept Clin Genet, Leeds LS9 7TF, W Yorkshire, England
[5] Gene Tech Lab 146 1, Lahore, Pakistan
[6] Fatima Jinah Med Coll, Dept Paediat, Lahore, Pakistan
[7] King Edward Med Univ, Dept Obstet & Gynaecol, Lahore, Pakistan
[8] United Arab Emirates Univ, Fac Med & Hlth Sci, Dept Paediat, Al Ain, U Arab Emirates
[9] Natl Ctr Diabet Endocrinol & Genet, Amman, Jordan
[10] CSS Mendel, I-00168 Rome, Italy
[11] IRCCS CSS, San Giovanni Rotondo, Italy
[12] St Lukes Hosp, Dept Paediat, Bradford BD5 0NA, W Yorkshire, England
[13] Pfizer Ltd, Global Res & Dev, Sandwich Labs, Sandwich CT13 9NJ, Kent, England
[14] UCL, Dept Biol, Mol Nocicept Grp, London WC1E 6BT, England
基金
英国医学研究理事会; 英国惠康基金;
关键词
D O I
10.1038/nature05413
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
The complete inability to sense pain in an otherwise healthy individual is a very rare phenotype. In three consanguineous families from northern Pakistan, we mapped the condition as an autosomal-recessive trait to chromosome 2q24.3. This region contains the gene SCN9A, encoding the alpha-subunit of the voltage-gated sodium channel, Na(v)1.7, which is strongly expressed in nociceptive neurons. Sequence analysis of SCN9A in affected individuals revealed three distinct homozygous nonsense mutations (S459X, I767X and W897X). We show that these mutations cause loss of function of Nav1.7 by co-expression of wild-type or mutant human Na(v)1.7 with sodium channel beta(1) and beta(2) subunits in HEK293 cells. In cells expressing mutant Nav1.7, the currents were no greater than background. Our data suggest that SCN9A is an essential and non-redundant requirement for nociception in humans. These findings should stimulate the search for novel analgesics that selectively target this sodium channel subunit.
引用
收藏
页码:894 / 898
页数:5
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