SRD5A3 Is Required for Converting Polyprenol to Dolichol and Is Mutated in a Congenital Glycosylation Disorder

Vincent Cantagrel; Dirk J. Lefeber; Bobby G. Ng; Ziqiang Guan; Jennifer L. Silhavy; Stephanie L. Bielas; Ludwig Lehle; Hans Hombauer; Maciej Adamowicz; Ewa Swiezewska; Arjan P. De Brouwer; Peter Blümel; Jolanta Sykut-Cegielska; Scott Houliston; Dominika Swistun; Bassam R. Ali; William B. Dobyns; Dusica Babovic-Vuksanovic; Hans van Bokhoven; Ron A. Wevers; Christian R.H. Raetz; Hudson H. Freeze; Éva Morava; Lihadh Al-Gazali; Joseph G. Gleeson

doi:10.1016/j.cell.2010.06.001

SRD5A3 Is Required for Converting Polyprenol to Dolichol and Is Mutated in a Congenital Glycosylation Disorder

Vincent Cantagrel, Dirk J. Lefeber, Bobby G. Ng, Ziqiang Guan, Jennifer L. Silhavy, Stephanie L. Bielas, Ludwig Lehle, Hans Hombauer, Maciej Adamowicz, Ewa Swiezewska, Arjan P. De Brouwer, Peter Blümel, Jolanta Sykut-Cegielska, Scott Houliston, Dominika Swistun, Bassam R. Ali, William B. Dobyns, Dusica Babovic-Vuksanovic, Hans van Bokhoven, Ron A. WeversChristian R.H. Raetz, Hudson H. Freeze, Éva Morava, Lihadh Al-Gazali, Joseph G. Gleeson

Research output: Contribution to journal › Article › peer-review

250 Scopus citations

Abstract

N-linked glycosylation is the most frequent modification of secreted and membrane-bound proteins in eukaryotic cells, disruption of which is the basis of the congenital disorders of glycosylation (CDGs). We describe a new type of CDG caused by mutations in the steroid 5α-reductase type 3 (SRD5A3) gene. Patients have mental retardation and ophthalmologic and cerebellar defects. We found that SRD5A3 is necessary for the reduction of the alpha-isoprene unit of polyprenols to form dolichols, required for synthesis of dolichol-linked monosaccharides, and the oligosaccharide precursor used for N-glycosylation. The presence of residual dolichol in cells depleted for this enzyme suggests the existence of an unexpected alternative pathway for dolichol de novo biosynthesis. Our results thus suggest that SRD5A3 is likely to be the long-sought polyprenol reductase and reveal the genetic basis of one of the earliest steps in protein N-linked glycosylation.

Original language	English
Pages (from-to)	203-217
Number of pages	15
Journal	Cell
Volume	142
Issue number	2
DOIs	https://doi.org/10.1016/j.cell.2010.06.001
State	Published - Jul 2010
Externally published	Yes

Keywords

Chembio
Humdisease

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Cantagrel, V., Lefeber, D. J., Ng, B. G., Guan, Z., Silhavy, J. L., Bielas, S. L., Lehle, L., Hombauer, H., Adamowicz, M., Swiezewska, E., De Brouwer, A. P., Blümel, P., Sykut-Cegielska, J., Houliston, S., Swistun, D., Ali, B. R., Dobyns, W. B., Babovic-Vuksanovic, D., van Bokhoven, H., ... Gleeson, J. G. (2010). SRD5A3 Is Required for Converting Polyprenol to Dolichol and Is Mutated in a Congenital Glycosylation Disorder. Cell, 142(2), 203-217. https://doi.org/10.1016/j.cell.2010.06.001

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title = "SRD5A3 Is Required for Converting Polyprenol to Dolichol and Is Mutated in a Congenital Glycosylation Disorder",

abstract = "N-linked glycosylation is the most frequent modification of secreted and membrane-bound proteins in eukaryotic cells, disruption of which is the basis of the congenital disorders of glycosylation (CDGs). We describe a new type of CDG caused by mutations in the steroid 5α-reductase type 3 (SRD5A3) gene. Patients have mental retardation and ophthalmologic and cerebellar defects. We found that SRD5A3 is necessary for the reduction of the alpha-isoprene unit of polyprenols to form dolichols, required for synthesis of dolichol-linked monosaccharides, and the oligosaccharide precursor used for N-glycosylation. The presence of residual dolichol in cells depleted for this enzyme suggests the existence of an unexpected alternative pathway for dolichol de novo biosynthesis. Our results thus suggest that SRD5A3 is likely to be the long-sought polyprenol reductase and reveal the genetic basis of one of the earliest steps in protein N-linked glycosylation.",

keywords = "Chembio, Humdisease",

author = "Vincent Cantagrel and Lefeber, {Dirk J.} and Ng, {Bobby G.} and Ziqiang Guan and Silhavy, {Jennifer L.} and Bielas, {Stephanie L.} and Ludwig Lehle and Hans Hombauer and Maciej Adamowicz and Ewa Swiezewska and {De Brouwer}, {Arjan P.} and Peter Bl{\"u}mel and Jolanta Sykut-Cegielska and Scott Houliston and Dominika Swistun and Ali, {Bassam R.} and Dobyns, {William B.} and Dusica Babovic-Vuksanovic and {van Bokhoven}, Hans and Wevers, {Ron A.} and Raetz, {Christian R.H.} and Freeze, {Hudson H.} and {\'E}va Morava and Lihadh Al-Gazali and Gleeson, {Joseph G.}",

year = "2010",

month = jul,

doi = "10.1016/j.cell.2010.06.001",

language = "English",

volume = "142",

pages = "203--217",

journal = "Cell",

issn = "0092-8674",

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Cantagrel, V, Lefeber, DJ, Ng, BG, Guan, Z, Silhavy, JL, Bielas, SL, Lehle, L, Hombauer, H, Adamowicz, M, Swiezewska, E, De Brouwer, AP, Blümel, P, Sykut-Cegielska, J, Houliston, S, Swistun, D, Ali, BR, Dobyns, WB, Babovic-Vuksanovic, D, van Bokhoven, H, Wevers, RA, Raetz, CRH, Freeze, HH, Morava, É, Al-Gazali, L & Gleeson, JG 2010, 'SRD5A3 Is Required for Converting Polyprenol to Dolichol and Is Mutated in a Congenital Glycosylation Disorder', Cell, vol. 142, no. 2, pp. 203-217. https://doi.org/10.1016/j.cell.2010.06.001

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AU - Cantagrel, Vincent

AU - Lefeber, Dirk J.

AU - Ng, Bobby G.

AU - Guan, Ziqiang

AU - Silhavy, Jennifer L.

AU - Bielas, Stephanie L.

AU - Lehle, Ludwig

AU - Hombauer, Hans

AU - Adamowicz, Maciej

AU - Swiezewska, Ewa

AU - De Brouwer, Arjan P.

AU - Blümel, Peter

AU - Sykut-Cegielska, Jolanta

AU - Houliston, Scott

AU - Swistun, Dominika

AU - Ali, Bassam R.

AU - Dobyns, William B.

AU - Babovic-Vuksanovic, Dusica

AU - van Bokhoven, Hans

AU - Wevers, Ron A.

AU - Raetz, Christian R.H.

AU - Freeze, Hudson H.

AU - Morava, Éva

AU - Al-Gazali, Lihadh

AU - Gleeson, Joseph G.

PY - 2010/7

Y1 - 2010/7

N2 - N-linked glycosylation is the most frequent modification of secreted and membrane-bound proteins in eukaryotic cells, disruption of which is the basis of the congenital disorders of glycosylation (CDGs). We describe a new type of CDG caused by mutations in the steroid 5α-reductase type 3 (SRD5A3) gene. Patients have mental retardation and ophthalmologic and cerebellar defects. We found that SRD5A3 is necessary for the reduction of the alpha-isoprene unit of polyprenols to form dolichols, required for synthesis of dolichol-linked monosaccharides, and the oligosaccharide precursor used for N-glycosylation. The presence of residual dolichol in cells depleted for this enzyme suggests the existence of an unexpected alternative pathway for dolichol de novo biosynthesis. Our results thus suggest that SRD5A3 is likely to be the long-sought polyprenol reductase and reveal the genetic basis of one of the earliest steps in protein N-linked glycosylation.

AB - N-linked glycosylation is the most frequent modification of secreted and membrane-bound proteins in eukaryotic cells, disruption of which is the basis of the congenital disorders of glycosylation (CDGs). We describe a new type of CDG caused by mutations in the steroid 5α-reductase type 3 (SRD5A3) gene. Patients have mental retardation and ophthalmologic and cerebellar defects. We found that SRD5A3 is necessary for the reduction of the alpha-isoprene unit of polyprenols to form dolichols, required for synthesis of dolichol-linked monosaccharides, and the oligosaccharide precursor used for N-glycosylation. The presence of residual dolichol in cells depleted for this enzyme suggests the existence of an unexpected alternative pathway for dolichol de novo biosynthesis. Our results thus suggest that SRD5A3 is likely to be the long-sought polyprenol reductase and reveal the genetic basis of one of the earliest steps in protein N-linked glycosylation.

KW - Chembio

KW - Humdisease

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U2 - 10.1016/j.cell.2010.06.001

DO - 10.1016/j.cell.2010.06.001

M3 - Article

C2 - 20637498

AN - SCOPUS:77955057089

SN - 0092-8674

VL - 142

SP - 203

EP - 217

JO - Cell

JF - Cell

IS - 2

ER -

SRD5A3 Is Required for Converting Polyprenol to Dolichol and Is Mutated in a Congenital Glycosylation Disorder

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