Mutation in SLC6A9 encoding a glycine transporter causes a novel form of non-ketotic hyperglycinemia in humans

被引：29

作者：

Alfadhel, Majid ^{[1
]}

Nashabat, Marwan ^{[1
]}

Al Qahtani, Hanan ^{[2
]}

Alfares, Ahmed ^{[3
]}

Al Mutairi, Fuad ^{[1
]}

Al Shaalan, Hesham ^{[2
]}

Douglas, Ganka V. ^{[4
]}

Wierenga, Klaas ^{[5
]}

Juusola, Jane ^{[4
]}

Alrifai, Muhammad Talal ^{[6
]}

Arold, Stefan T. ^{[7
]}

Alkuraya, Fowzan ^{[8
,9
]}

Abu Ali, Qais ^{[4
]}

机构：

[1] King Saud bin Abdulaziz Univ Hlth Sci, Div Genet, Dept Pediat, King Abdullah Int Med Res Ctr,Minist Natl Guard H, POB 22490, Riyadh 11426, Saudi Arabia

[2] King Saud bin Abdulaziz Univ Hlth Sci, Dept Med Imaging, King Abdullah Int Med Res Ctr, Minist Natl Guard Hlth Affairs NGHA, Riyadh, Saudi Arabia

[3] Qassim Univ, Dept Pediat, Coll Med, Almulyda, Saudi Arabia

[4] GeneDx, Gaithersburg, MD 20877 USA

[5] OUHSC, Genet Sect, Dept Pediat, Oklahoma City, OK USA

[6] King Saud bin Abdulaziz Univ Hlth Sci, Div Neurol, Dept Pediat, King Abdullah Int Med Res Ctr,Minist Natl Guard H, Riyadh, Saudi Arabia

[7] King Abdullah Univ Sci & Technol KAUST, Div Biol & Environm Sci & Engn BESE, Computat Biosci Res Ctr CBRC, Thuwal 239556900, Saudi Arabia

[8] King Faisal Specialist Hosp & Res Ctr, Dept Genet, Riyadh, Saudi Arabia

[9] Alfaisal Univ, Dept Anat & Cell Biol, Coll Med, Riyadh, Saudi Arabia

来源：

HUMAN GENETICS | 2016年 / 135卷 / 11期

关键词：

ENCEPHALOPATHY; METABOLISM; STARTLE;

D O I：

10.1007/s00439-016-1719-x

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Glycine cleavage system (GCS) catalyzes the degradation of glycine and disruption of its components encoded by GLDC, AMT and GCSH are the only known causes of glycine encephalopathy, also known as non-ketotic hyperglycinemia (NKH). In this report, we describe a consanguineous family with one child who presented with NKH, but harbored no pathogenic variants in any of the three genes linked to this condition. Whole-exome sequencing revealed a novel homozygous missense variant in exon 9 of SLC6A9 NM_201649.3: c.1219 A > G (p.Ser407Gly) that segregates with the disease within the family. This variant replaces the highly conserved S407 in the ion-binding site of this glycine transporter and is predicted to disrupt its function. In murine model, knockout of Slc6a9 is associated with equivalent phenotype of NKH, namely respiratory distress and hypotonia. This is the first demonstration that mutation of the glycine transporter can be associated with NKH in humans.

引用

页码：1263 / 1268

页数：6

共 20 条

[1] THE CONCISE GUIDE TO PHARMACOLOGY 2015/16: Transporters [J].

Alexander, Stephen P. H. ;

Kelly, Eamonn ;

Marrion, Neil ;

Peters, John A. ;

Benson, Helen E. ;

Faccenda, Elena ;

Pawson, Adam J. ;

Sharman, Joanna L. ;

Southan, Christopher ;

Davies, Jamie A. ;

Aldrich, R. ;

Attali, B. ;

Back, M. ;

Barnes, N. M. ;

Bathgate, R. ;

Beart, P. M. ;

Becirovic, E. ;

Biel, M. ;

Birdsall, N. J. ;

Boison, D. ;

Brauner-Osborne, H. ;

Broeer, S. ;

Bryant, C. ;

Burnstock, G. ;

Burris, T. ;

Cain, D. ;

Calo, G. ;

Chan, S. L. ;

Chandy, K. G. ;

Chiang, N. ;

Christakos, S. ;

Christopoulos, A. ;

Chun, J. J. ;

Chung, J. -J. ;

Clapham, D. E. ;

Connor, M. A. ;

Coons, L. ;

Cox, H. M. ;

Dautzenberg, F. M. ;

Dent, G. ;

Douglas, S. D. ;

Dubocovich, M. L. ;

Edwards, D. P. ;

Farndale, R. ;

Fong, T. M. ;

Forrest, D. ;

Fowler, C. J. ;

Fuller, P. ;

Gainetdinov, R. R. ;

Gershengorn, M. A. .

BRITISH JOURNAL OF PHARMACOLOGY, 2015, 172 (24) :6110-6202

[2] Glycine encephalopathy (nonketotic hyperglycinemia): Comments and speculations [J].

Applegarth, DA ;

Toone, JR .

AMERICAN JOURNAL OF MEDICAL GENETICS PART A, 2006, 140A (02) :186-188

[3] The SWISS-MODEL workspace: a web-based environment for protein structure homology modelling [J].

Arnold, K ;

Bordoli, L ;

Kopp, J ;

Schwede, T .

BIOINFORMATICS, 2006, 22 (02) :195-201

[4] Molecular Basis of the Dominant Negative Effect of a Glycine Transporter 2 Mutation Associated with Hyperekplexia [J].

Arribas-Gonzalez, Esther ;

de Juan-Sanz, Jaime ;

Aragon, Carmen ;

Lopez-Corcuera, Beatriz .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2015, 290 (04) :2150-2165

[5] Glycine transporters: essential regulators of synaptic transmission [J].

Betz, H ;

Gomeza, J ;

Armsen, W ;

Scholze, P ;

Eulenburg, V .

BIOCHEMICAL SOCIETY TRANSACTIONS, 2006, 34 :55-58

[6] The specification of glycinergic neurons and the role of glycinergic transmission in development [J].

Chalphin, Alexander V. ;

Saha, Margaret S. .

FRONTIERS IN MOLECULAR NEUROSCIENCE, 2010, 3

[7] Nitric oxide and energy metabolism in mammals [J].

Dai, Zhaolai ;

Wu, Zhenlong ;

Yang, Ying ;

Wang, Junjun ;

Satterfield, M. Carey ;

Meininger, Cynthia J. ;

Bazer, Fuller W. ;

Wu, Guoyao .

BIOFACTORS, 2013, 39 (04) :383-391

[8] GLYCINE ENCEPHALOPATHY [J].

DALLABERNARDINA, B ;

AICARDI, J ;

GOUTIERES, F ;

PLOUIN, P .

NEUROPADIATRIE, 1979, 10 (03) :209-225

[9] FEAR-POTENTIATED STARTLE - A NEURAL AND PHARMACOLOGICAL ANALYSIS [J].

DAVIS, M ;

FALLS, WA ;

CAMPEAU, S ;

KIM, M .

BEHAVIOURAL BRAIN RESEARCH, 1993, 58 (1-2) :175-198

[10] The startle syndromes: Physiology and treatment [J].

Dreissen, Yasmine E. M. ;

Tijssen, Marina A. J. .

EPILEPSIA, 2012, 53 :3-11

← 1 2 →