Altered PLP1 splicing causes hypomyelination of early myelinating structures

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Altered PLP1 splicing causes hypomyelination of early myelinating structures. / Kevelam, Sietske H; Taube, Jennifer R; van Spaendonk, Rosalina M L; Bertini, Enrico; Sperle, Karen; Tarnopolsky, Mark; Tonduti, Davide; Valente, Enza Maria; Travaglini, Lorena; Sistermans, Erik A; Bernard, Geneviève; Catsman-Berrevoets, Coriene E; van Karnebeek, Clara D M; Østergaard, John R; Friederich, Richard L; Fawzi Elsaid, Mahmoud; Schieving, Jolanda H; Tarailo-Graovac, Maja; Orcesi, Simona; Steenweg, Marjan E; van Berkel, Carola G M; Waisfisz, Quinten; Abbink, Truus E M; van der Knaap, Marjo S; Hobson, Grace M; Wolf, Nicole I.

In: Annals of clinical and translational neurology, Vol. 2, No. 6, 02.06.2015, p. 648-61.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

Harvard

Kevelam, SH, Taube, JR, van Spaendonk, RML, Bertini, E, Sperle, K, Tarnopolsky, M, Tonduti, D, Valente, EM, Travaglini, L, Sistermans, EA, Bernard, G, Catsman-Berrevoets, CE, van Karnebeek, CDM, Østergaard, JR, Friederich, RL, Fawzi Elsaid, M, Schieving, JH, Tarailo-Graovac, M, Orcesi, S, Steenweg, ME, van Berkel, CGM, Waisfisz, Q, Abbink, TEM, van der Knaap, MS, Hobson, GM & Wolf, NI 2015, 'Altered PLP1 splicing causes hypomyelination of early myelinating structures', Annals of clinical and translational neurology, vol. 2, no. 6, pp. 648-61. https://doi.org/10.1002/acn3.203

APA

Kevelam, S. H., Taube, J. R., van Spaendonk, R. M. L., Bertini, E., Sperle, K., Tarnopolsky, M., Tonduti, D., Valente, E. M., Travaglini, L., Sistermans, E. A., Bernard, G., Catsman-Berrevoets, C. E., van Karnebeek, C. D. M., Østergaard, J. R., Friederich, R. L., Fawzi Elsaid, M., Schieving, J. H., Tarailo-Graovac, M., Orcesi, S., ... Wolf, N. I. (2015). Altered PLP1 splicing causes hypomyelination of early myelinating structures. Annals of clinical and translational neurology, 2(6), 648-61. https://doi.org/10.1002/acn3.203

CBE

Kevelam SH, Taube JR, van Spaendonk RML, Bertini E, Sperle K, Tarnopolsky M, Tonduti D, Valente EM, Travaglini L, Sistermans EA, Bernard G, Catsman-Berrevoets CE, van Karnebeek CDM, Østergaard JR, Friederich RL, Fawzi Elsaid M, Schieving JH, Tarailo-Graovac M, Orcesi S, Steenweg ME, van Berkel CGM, Waisfisz Q, Abbink TEM, van der Knaap MS, Hobson GM, Wolf NI. 2015. Altered PLP1 splicing causes hypomyelination of early myelinating structures. Annals of clinical and translational neurology. 2(6):648-61. https://doi.org/10.1002/acn3.203

MLA

Kevelam, Sietske H et al. "Altered PLP1 splicing causes hypomyelination of early myelinating structures". Annals of clinical and translational neurology. 2015, 2(6). 648-61. https://doi.org/10.1002/acn3.203

Vancouver

Kevelam SH, Taube JR, van Spaendonk RML, Bertini E, Sperle K, Tarnopolsky M et al. Altered PLP1 splicing causes hypomyelination of early myelinating structures. Annals of clinical and translational neurology. 2015 Jun 2;2(6):648-61. https://doi.org/10.1002/acn3.203

Author

Kevelam, Sietske H ; Taube, Jennifer R ; van Spaendonk, Rosalina M L ; Bertini, Enrico ; Sperle, Karen ; Tarnopolsky, Mark ; Tonduti, Davide ; Valente, Enza Maria ; Travaglini, Lorena ; Sistermans, Erik A ; Bernard, Geneviève ; Catsman-Berrevoets, Coriene E ; van Karnebeek, Clara D M ; Østergaard, John R ; Friederich, Richard L ; Fawzi Elsaid, Mahmoud ; Schieving, Jolanda H ; Tarailo-Graovac, Maja ; Orcesi, Simona ; Steenweg, Marjan E ; van Berkel, Carola G M ; Waisfisz, Quinten ; Abbink, Truus E M ; van der Knaap, Marjo S ; Hobson, Grace M ; Wolf, Nicole I. / Altered PLP1 splicing causes hypomyelination of early myelinating structures. In: Annals of clinical and translational neurology. 2015 ; Vol. 2, No. 6. pp. 648-61.

Bibtex

@article{b11de5eace604991975891e38a99e60c,
title = "Altered PLP1 splicing causes hypomyelination of early myelinating structures",
abstract = "OBJECTIVE: The objective of this study was to investigate the genetic etiology of the X-linked disorder {"}Hypomyelination of Early Myelinating Structures{"} (HEMS).METHODS: We included 16 patients from 10 families diagnosed with HEMS by brain MRI criteria. Exome sequencing was used to search for causal mutations. In silico analysis of effects of the mutations on splicing and RNA folding was performed. In vitro gene splicing was examined in RNA from patients' fibroblasts and an immortalized immature oligodendrocyte cell line after transfection with mutant minigene splicing constructs.RESULTS: All patients had unusual hemizygous mutations of PLP1 located in exon 3B (one deletion, one missense and two silent), which is spliced out in isoform DM20, or in intron 3 (five mutations). The deletion led to truncation of PLP1, but not DM20. Four mutations were predicted to affect PLP1/DM20 alternative splicing by creating exonic splicing silencer motifs or new splice donor sites or by affecting the local RNA structure of the PLP1 splice donor site. Four deep intronic mutations were predicted to destabilize a long-distance interaction structure in the secondary PLP1 RNA fragment involved in regulating PLP1/DM20 alternative splicing. Splicing studies in fibroblasts and transfected cells confirmed a decreased PLP1/DM20 ratio.INTERPRETATION: Brain structures that normally myelinate early are poorly myelinated in HEMS, while they are the best myelinated structures in Pelizaeus-Merzbacher disease, also caused by PLP1 alterations. Our data extend the phenotypic spectrum of PLP1-related disorders indicating that normal PLP1/DM20 alternative splicing is essential for early myelination and support the need to include intron 3 in diagnostic sequencing.",
author = "Kevelam, {Sietske H} and Taube, {Jennifer R} and {van Spaendonk}, {Rosalina M L} and Enrico Bertini and Karen Sperle and Mark Tarnopolsky and Davide Tonduti and Valente, {Enza Maria} and Lorena Travaglini and Sistermans, {Erik A} and Genevi{\`e}ve Bernard and Catsman-Berrevoets, {Coriene E} and {van Karnebeek}, {Clara D M} and {\O}stergaard, {John R} and Friederich, {Richard L} and {Fawzi Elsaid}, Mahmoud and Schieving, {Jolanda H} and Maja Tarailo-Graovac and Simona Orcesi and Steenweg, {Marjan E} and {van Berkel}, {Carola G M} and Quinten Waisfisz and Abbink, {Truus E M} and {van der Knaap}, {Marjo S} and Hobson, {Grace M} and Wolf, {Nicole I}",
year = "2015",
month = jun,
day = "2",
doi = "10.1002/acn3.203",
language = "English",
volume = "2",
pages = "648--61",
journal = "Annals of clinical and translational neurology",
issn = "2328-9503",
publisher = "John Wiley and Sons Ltd",
number = "6",

}

RIS

TY - JOUR

T1 - Altered PLP1 splicing causes hypomyelination of early myelinating structures

AU - Kevelam, Sietske H

AU - Taube, Jennifer R

AU - van Spaendonk, Rosalina M L

AU - Bertini, Enrico

AU - Sperle, Karen

AU - Tarnopolsky, Mark

AU - Tonduti, Davide

AU - Valente, Enza Maria

AU - Travaglini, Lorena

AU - Sistermans, Erik A

AU - Bernard, Geneviève

AU - Catsman-Berrevoets, Coriene E

AU - van Karnebeek, Clara D M

AU - Østergaard, John R

AU - Friederich, Richard L

AU - Fawzi Elsaid, Mahmoud

AU - Schieving, Jolanda H

AU - Tarailo-Graovac, Maja

AU - Orcesi, Simona

AU - Steenweg, Marjan E

AU - van Berkel, Carola G M

AU - Waisfisz, Quinten

AU - Abbink, Truus E M

AU - van der Knaap, Marjo S

AU - Hobson, Grace M

AU - Wolf, Nicole I

PY - 2015/6/2

Y1 - 2015/6/2

N2 - OBJECTIVE: The objective of this study was to investigate the genetic etiology of the X-linked disorder "Hypomyelination of Early Myelinating Structures" (HEMS).METHODS: We included 16 patients from 10 families diagnosed with HEMS by brain MRI criteria. Exome sequencing was used to search for causal mutations. In silico analysis of effects of the mutations on splicing and RNA folding was performed. In vitro gene splicing was examined in RNA from patients' fibroblasts and an immortalized immature oligodendrocyte cell line after transfection with mutant minigene splicing constructs.RESULTS: All patients had unusual hemizygous mutations of PLP1 located in exon 3B (one deletion, one missense and two silent), which is spliced out in isoform DM20, or in intron 3 (five mutations). The deletion led to truncation of PLP1, but not DM20. Four mutations were predicted to affect PLP1/DM20 alternative splicing by creating exonic splicing silencer motifs or new splice donor sites or by affecting the local RNA structure of the PLP1 splice donor site. Four deep intronic mutations were predicted to destabilize a long-distance interaction structure in the secondary PLP1 RNA fragment involved in regulating PLP1/DM20 alternative splicing. Splicing studies in fibroblasts and transfected cells confirmed a decreased PLP1/DM20 ratio.INTERPRETATION: Brain structures that normally myelinate early are poorly myelinated in HEMS, while they are the best myelinated structures in Pelizaeus-Merzbacher disease, also caused by PLP1 alterations. Our data extend the phenotypic spectrum of PLP1-related disorders indicating that normal PLP1/DM20 alternative splicing is essential for early myelination and support the need to include intron 3 in diagnostic sequencing.

AB - OBJECTIVE: The objective of this study was to investigate the genetic etiology of the X-linked disorder "Hypomyelination of Early Myelinating Structures" (HEMS).METHODS: We included 16 patients from 10 families diagnosed with HEMS by brain MRI criteria. Exome sequencing was used to search for causal mutations. In silico analysis of effects of the mutations on splicing and RNA folding was performed. In vitro gene splicing was examined in RNA from patients' fibroblasts and an immortalized immature oligodendrocyte cell line after transfection with mutant minigene splicing constructs.RESULTS: All patients had unusual hemizygous mutations of PLP1 located in exon 3B (one deletion, one missense and two silent), which is spliced out in isoform DM20, or in intron 3 (five mutations). The deletion led to truncation of PLP1, but not DM20. Four mutations were predicted to affect PLP1/DM20 alternative splicing by creating exonic splicing silencer motifs or new splice donor sites or by affecting the local RNA structure of the PLP1 splice donor site. Four deep intronic mutations were predicted to destabilize a long-distance interaction structure in the secondary PLP1 RNA fragment involved in regulating PLP1/DM20 alternative splicing. Splicing studies in fibroblasts and transfected cells confirmed a decreased PLP1/DM20 ratio.INTERPRETATION: Brain structures that normally myelinate early are poorly myelinated in HEMS, while they are the best myelinated structures in Pelizaeus-Merzbacher disease, also caused by PLP1 alterations. Our data extend the phenotypic spectrum of PLP1-related disorders indicating that normal PLP1/DM20 alternative splicing is essential for early myelination and support the need to include intron 3 in diagnostic sequencing.

U2 - 10.1002/acn3.203

DO - 10.1002/acn3.203

M3 - Journal article

C2 - 26125040

VL - 2

SP - 648

EP - 661

JO - Annals of clinical and translational neurology

JF - Annals of clinical and translational neurology

SN - 2328-9503

IS - 6

ER -