Mutations in U4atac snRNA, a component of the minor spliceosome, in the developmental disorder MOPD i

Huiling He; Sandya Liyanarachchi; Keiko Akagi; Rebecca Nagy; Jingfeng Li; Rosemary C. Dietrich; Wei Li; Nikhil Sebastian; Bernard Wen; Baozhong Xin; Jarnail Singh; Pearlly Yan; Hansjuerg Alder; Eric Haan; Dagmar Wieczorek; Beate Albrecht; Erik Puffenberger; Heng Wang; Judith A. Westman; Richard A. Padgett; David E. Symer; Albert De La Chapelle

doi:10.1126/science.1200587

Mutations in U4atac snRNA, a component of the minor spliceosome, in the developmental disorder MOPD i

Huiling He, Sandya Liyanarachchi, Keiko Akagi, Rebecca Nagy, Jingfeng Li, Rosemary C. Dietrich, Wei Li, Nikhil Sebastian, Bernard Wen, Baozhong Xin, Jarnail Singh, Pearlly Yan, Hansjuerg Alder, Eric Haan, Dagmar Wieczorek, Beate Albrecht, Erik Puffenberger, Heng Wang, Judith A. Westman, Richard A. PadgettDavid E. Symer, Albert De La Chapelle

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189 Scopus citations

Abstract

Small nuclear RNAs (snRNAs) are essential factors in messenger RNA splicing. By means of homozygosity mapping and deep sequencing, we show that a gene encoding U4atac snRNA, a component of the minor U12-dependent spliceosome, is mutated in individuals with microcephalic osteodysplastic primordial dwarfism type I (MOPD I), a severe developmental disorder characterized by extreme intrauterine growth retardation and multiple organ abnormalities. Functional assays showed that mutations (30G>A, 51G>A, 55G>A, and 111G>A) associated with MOPD I cause defective U12-dependent splicing. Endogenous U12-dependent but not U2-dependent introns were found to be poorly spliced in MOPD I patient fibroblast cells. The introduction of wild-type U4atac snRNA into MOPD I cells enhanced U12-dependent splicing. These results illustrate the critical role of minor intron splicing in human development.

Original language	English (US)
Pages (from-to)	238-240
Number of pages	3
Journal	Science
Volume	332
Issue number	6026
DOIs	https://doi.org/10.1126/science.1200587
State	Published - Apr 8 2011
Externally published	Yes

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He, H., Liyanarachchi, S., Akagi, K., Nagy, R., Li, J., Dietrich, R. C., Li, W., Sebastian, N., Wen, B., Xin, B., Singh, J., Yan, P., Alder, H., Haan, E., Wieczorek, D., Albrecht, B., Puffenberger, E., Wang, H., Westman, J. A., ... De La Chapelle, A. (2011). Mutations in U4atac snRNA, a component of the minor spliceosome, in the developmental disorder MOPD i. Science, 332(6026), 238-240. https://doi.org/10.1126/science.1200587

He, H, Liyanarachchi, S, Akagi, K, Nagy, R, Li, J, Dietrich, RC, Li, W, Sebastian, N, Wen, B, Xin, B, Singh, J, Yan, P, Alder, H, Haan, E, Wieczorek, D, Albrecht, B, Puffenberger, E, Wang, H, Westman, JA, Padgett, RA, Symer, DE & De La Chapelle, A 2011, 'Mutations in U4atac snRNA, a component of the minor spliceosome, in the developmental disorder MOPD i', Science, vol. 332, no. 6026, pp. 238-240. https://doi.org/10.1126/science.1200587

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abstract = "Small nuclear RNAs (snRNAs) are essential factors in messenger RNA splicing. By means of homozygosity mapping and deep sequencing, we show that a gene encoding U4atac snRNA, a component of the minor U12-dependent spliceosome, is mutated in individuals with microcephalic osteodysplastic primordial dwarfism type I (MOPD I), a severe developmental disorder characterized by extreme intrauterine growth retardation and multiple organ abnormalities. Functional assays showed that mutations (30G>A, 51G>A, 55G>A, and 111G>A) associated with MOPD I cause defective U12-dependent splicing. Endogenous U12-dependent but not U2-dependent introns were found to be poorly spliced in MOPD I patient fibroblast cells. The introduction of wild-type U4atac snRNA into MOPD I cells enhanced U12-dependent splicing. These results illustrate the critical role of minor intron splicing in human development.",

author = "Huiling He and Sandya Liyanarachchi and Keiko Akagi and Rebecca Nagy and Jingfeng Li and Dietrich, {Rosemary C.} and Wei Li and Nikhil Sebastian and Bernard Wen and Baozhong Xin and Jarnail Singh and Pearlly Yan and Hansjuerg Alder and Eric Haan and Dagmar Wieczorek and Beate Albrecht and Erik Puffenberger and Heng Wang and Westman, {Judith A.} and Padgett, {Richard A.} and Symer, {David E.} and {De La Chapelle}, Albert",

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AU - He, Huiling

AU - Liyanarachchi, Sandya

AU - Akagi, Keiko

AU - Nagy, Rebecca

AU - Li, Jingfeng

AU - Dietrich, Rosemary C.

AU - Li, Wei

AU - Sebastian, Nikhil

AU - Wen, Bernard

AU - Xin, Baozhong

AU - Singh, Jarnail

AU - Yan, Pearlly

AU - Alder, Hansjuerg

AU - Haan, Eric

AU - Wieczorek, Dagmar

AU - Albrecht, Beate

AU - Puffenberger, Erik

AU - Wang, Heng

AU - Westman, Judith A.

AU - Padgett, Richard A.

AU - Symer, David E.

AU - De La Chapelle, Albert

PY - 2011/4/8

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N2 - Small nuclear RNAs (snRNAs) are essential factors in messenger RNA splicing. By means of homozygosity mapping and deep sequencing, we show that a gene encoding U4atac snRNA, a component of the minor U12-dependent spliceosome, is mutated in individuals with microcephalic osteodysplastic primordial dwarfism type I (MOPD I), a severe developmental disorder characterized by extreme intrauterine growth retardation and multiple organ abnormalities. Functional assays showed that mutations (30G>A, 51G>A, 55G>A, and 111G>A) associated with MOPD I cause defective U12-dependent splicing. Endogenous U12-dependent but not U2-dependent introns were found to be poorly spliced in MOPD I patient fibroblast cells. The introduction of wild-type U4atac snRNA into MOPD I cells enhanced U12-dependent splicing. These results illustrate the critical role of minor intron splicing in human development.

AB - Small nuclear RNAs (snRNAs) are essential factors in messenger RNA splicing. By means of homozygosity mapping and deep sequencing, we show that a gene encoding U4atac snRNA, a component of the minor U12-dependent spliceosome, is mutated in individuals with microcephalic osteodysplastic primordial dwarfism type I (MOPD I), a severe developmental disorder characterized by extreme intrauterine growth retardation and multiple organ abnormalities. Functional assays showed that mutations (30G>A, 51G>A, 55G>A, and 111G>A) associated with MOPD I cause defective U12-dependent splicing. Endogenous U12-dependent but not U2-dependent introns were found to be poorly spliced in MOPD I patient fibroblast cells. The introduction of wild-type U4atac snRNA into MOPD I cells enhanced U12-dependent splicing. These results illustrate the critical role of minor intron splicing in human development.

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Mutations in U4atac snRNA, a component of the minor spliceosome, in the developmental disorder MOPD i

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