Mutations in SPAG1 cause primary ciliary dyskinesia associated with defective outer and inner dynein arms

Michael R. Knowles, Lawrence E. Ostrowski, Niki T. Loges, Toby Hurd, Margaret W. Leigh, Lu Huang, Whitney E. Wolf, Johnny L. Carson, Milan J. Hazucha, Weining Yin, Stephanie Davis, Sharon D. Dell, Thomas W. Ferkol, Scott D. Sagel, Kenneth N. Olivier, Charlotte Jahnke, Heike Olbrich, Claudius Werner, Johanna Raidt, Julia WallmeierPetra Pennekamp, Gerard W. Dougherty, Rim Hjeij, Heon Yung Gee, Edgar A. Otto, Jan Halbritter, Moumita Chaki, Katrina A. Diaz, Daniela A. Braun, Jonathan D. Porath, Markus Schueler, György Baktai, Matthias Griese, Emily H. Turner, Alexandra P. Lewis, Michael J. Bamshad, Deborah A. Nickerson, Friedhelm Hildebrandt, Jay Shendure, Heymut Omran, Maimoona A. Zariwala

Research output: Contribution to journalArticle

65 Citations (Scopus)

Abstract

Primary ciliary dyskinesia (PCD) is a genetically heterogeneous, autosomal-recessive disorder, characterized by oto-sino-pulmonary disease and situs abnormalities. PCD-causing mutations have been identified in 20 genes, but collectively they account for only ∼65% of all PCDs. To identify mutations in additional genes that cause PCD, we performed exome sequencing on three unrelated probands with ciliary outer and inner dynein arm (ODA+IDA) defects. Mutations in SPAG1 were identified in one family with three affected siblings. Further screening of SPAG1 in 98 unrelated affected individuals (62 with ODA+IDA defects, 35 with ODA defects, 1 without available ciliary ultrastructure) revealed biallelic loss-of-function mutations in 11 additional individuals (including one sib-pair). All 14 affected individuals with SPAG1 mutations had a characteristic PCD phenotype, including 8 with situs abnormalities. Additionally, all individuals with mutations who had defined ciliary ultrastructure had ODA+IDA defects. SPAG1 was present in human airway epithelial cell lysates but was not present in isolated axonemes, and immunofluorescence staining showed an absence of ODA and IDA proteins in cilia from an affected individual, thus indicating that SPAG1 probably plays a role in the cytoplasmic assembly and/or trafficking of the axonemal dynein arms. Zebrafish morpholino studies of spag1 produced cilia-related phenotypes previously reported for PCD-causing mutations in genes encoding cytoplasmic proteins. Together, these results demonstrate that mutations in SPAG1 cause PCD with ciliary ODA+IDA defects and that exome sequencing is useful to identify genetic causes of heterogeneous recessive disorders.

Original languageEnglish
Pages (from-to)711-720
Number of pages10
JournalAmerican Journal of Human Genetics
Volume93
Issue number4
DOIs
StatePublished - Oct 3 2013

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Kartagener Syndrome
Dyneins
Mutation
Exome
Cilia
Axonemal Dyneins
Genes
Axoneme
Phenotype
Morpholinos
Zebrafish
Lung Diseases
Fluorescent Antibody Technique
Proteins
Epithelial Cells
Staining and Labeling

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Knowles, M. R., Ostrowski, L. E., Loges, N. T., Hurd, T., Leigh, M. W., Huang, L., ... Zariwala, M. A. (2013). Mutations in SPAG1 cause primary ciliary dyskinesia associated with defective outer and inner dynein arms. American Journal of Human Genetics, 93(4), 711-720. https://doi.org/10.1016/j.ajhg.2013.07.025

Mutations in SPAG1 cause primary ciliary dyskinesia associated with defective outer and inner dynein arms. / Knowles, Michael R.; Ostrowski, Lawrence E.; Loges, Niki T.; Hurd, Toby; Leigh, Margaret W.; Huang, Lu; Wolf, Whitney E.; Carson, Johnny L.; Hazucha, Milan J.; Yin, Weining; Davis, Stephanie; Dell, Sharon D.; Ferkol, Thomas W.; Sagel, Scott D.; Olivier, Kenneth N.; Jahnke, Charlotte; Olbrich, Heike; Werner, Claudius; Raidt, Johanna; Wallmeier, Julia; Pennekamp, Petra; Dougherty, Gerard W.; Hjeij, Rim; Gee, Heon Yung; Otto, Edgar A.; Halbritter, Jan; Chaki, Moumita; Diaz, Katrina A.; Braun, Daniela A.; Porath, Jonathan D.; Schueler, Markus; Baktai, György; Griese, Matthias; Turner, Emily H.; Lewis, Alexandra P.; Bamshad, Michael J.; Nickerson, Deborah A.; Hildebrandt, Friedhelm; Shendure, Jay; Omran, Heymut; Zariwala, Maimoona A.

In: American Journal of Human Genetics, Vol. 93, No. 4, 03.10.2013, p. 711-720.

Research output: Contribution to journalArticle

Knowles, MR, Ostrowski, LE, Loges, NT, Hurd, T, Leigh, MW, Huang, L, Wolf, WE, Carson, JL, Hazucha, MJ, Yin, W, Davis, S, Dell, SD, Ferkol, TW, Sagel, SD, Olivier, KN, Jahnke, C, Olbrich, H, Werner, C, Raidt, J, Wallmeier, J, Pennekamp, P, Dougherty, GW, Hjeij, R, Gee, HY, Otto, EA, Halbritter, J, Chaki, M, Diaz, KA, Braun, DA, Porath, JD, Schueler, M, Baktai, G, Griese, M, Turner, EH, Lewis, AP, Bamshad, MJ, Nickerson, DA, Hildebrandt, F, Shendure, J, Omran, H & Zariwala, MA 2013, 'Mutations in SPAG1 cause primary ciliary dyskinesia associated with defective outer and inner dynein arms', American Journal of Human Genetics, vol. 93, no. 4, pp. 711-720. https://doi.org/10.1016/j.ajhg.2013.07.025
Knowles, Michael R. ; Ostrowski, Lawrence E. ; Loges, Niki T. ; Hurd, Toby ; Leigh, Margaret W. ; Huang, Lu ; Wolf, Whitney E. ; Carson, Johnny L. ; Hazucha, Milan J. ; Yin, Weining ; Davis, Stephanie ; Dell, Sharon D. ; Ferkol, Thomas W. ; Sagel, Scott D. ; Olivier, Kenneth N. ; Jahnke, Charlotte ; Olbrich, Heike ; Werner, Claudius ; Raidt, Johanna ; Wallmeier, Julia ; Pennekamp, Petra ; Dougherty, Gerard W. ; Hjeij, Rim ; Gee, Heon Yung ; Otto, Edgar A. ; Halbritter, Jan ; Chaki, Moumita ; Diaz, Katrina A. ; Braun, Daniela A. ; Porath, Jonathan D. ; Schueler, Markus ; Baktai, György ; Griese, Matthias ; Turner, Emily H. ; Lewis, Alexandra P. ; Bamshad, Michael J. ; Nickerson, Deborah A. ; Hildebrandt, Friedhelm ; Shendure, Jay ; Omran, Heymut ; Zariwala, Maimoona A. / Mutations in SPAG1 cause primary ciliary dyskinesia associated with defective outer and inner dynein arms. In: American Journal of Human Genetics. 2013 ; Vol. 93, No. 4. pp. 711-720.
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abstract = "Primary ciliary dyskinesia (PCD) is a genetically heterogeneous, autosomal-recessive disorder, characterized by oto-sino-pulmonary disease and situs abnormalities. PCD-causing mutations have been identified in 20 genes, but collectively they account for only ∼65{\%} of all PCDs. To identify mutations in additional genes that cause PCD, we performed exome sequencing on three unrelated probands with ciliary outer and inner dynein arm (ODA+IDA) defects. Mutations in SPAG1 were identified in one family with three affected siblings. Further screening of SPAG1 in 98 unrelated affected individuals (62 with ODA+IDA defects, 35 with ODA defects, 1 without available ciliary ultrastructure) revealed biallelic loss-of-function mutations in 11 additional individuals (including one sib-pair). All 14 affected individuals with SPAG1 mutations had a characteristic PCD phenotype, including 8 with situs abnormalities. Additionally, all individuals with mutations who had defined ciliary ultrastructure had ODA+IDA defects. SPAG1 was present in human airway epithelial cell lysates but was not present in isolated axonemes, and immunofluorescence staining showed an absence of ODA and IDA proteins in cilia from an affected individual, thus indicating that SPAG1 probably plays a role in the cytoplasmic assembly and/or trafficking of the axonemal dynein arms. Zebrafish morpholino studies of spag1 produced cilia-related phenotypes previously reported for PCD-causing mutations in genes encoding cytoplasmic proteins. Together, these results demonstrate that mutations in SPAG1 cause PCD with ciliary ODA+IDA defects and that exome sequencing is useful to identify genetic causes of heterogeneous recessive disorders.",
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T1 - Mutations in SPAG1 cause primary ciliary dyskinesia associated with defective outer and inner dynein arms

AU - Knowles, Michael R.

AU - Ostrowski, Lawrence E.

AU - Loges, Niki T.

AU - Hurd, Toby

AU - Leigh, Margaret W.

AU - Huang, Lu

AU - Wolf, Whitney E.

AU - Carson, Johnny L.

AU - Hazucha, Milan J.

AU - Yin, Weining

AU - Davis, Stephanie

AU - Dell, Sharon D.

AU - Ferkol, Thomas W.

AU - Sagel, Scott D.

AU - Olivier, Kenneth N.

AU - Jahnke, Charlotte

AU - Olbrich, Heike

AU - Werner, Claudius

AU - Raidt, Johanna

AU - Wallmeier, Julia

AU - Pennekamp, Petra

AU - Dougherty, Gerard W.

AU - Hjeij, Rim

AU - Gee, Heon Yung

AU - Otto, Edgar A.

AU - Halbritter, Jan

AU - Chaki, Moumita

AU - Diaz, Katrina A.

AU - Braun, Daniela A.

AU - Porath, Jonathan D.

AU - Schueler, Markus

AU - Baktai, György

AU - Griese, Matthias

AU - Turner, Emily H.

AU - Lewis, Alexandra P.

AU - Bamshad, Michael J.

AU - Nickerson, Deborah A.

AU - Hildebrandt, Friedhelm

AU - Shendure, Jay

AU - Omran, Heymut

AU - Zariwala, Maimoona A.

PY - 2013/10/3

Y1 - 2013/10/3

N2 - Primary ciliary dyskinesia (PCD) is a genetically heterogeneous, autosomal-recessive disorder, characterized by oto-sino-pulmonary disease and situs abnormalities. PCD-causing mutations have been identified in 20 genes, but collectively they account for only ∼65% of all PCDs. To identify mutations in additional genes that cause PCD, we performed exome sequencing on three unrelated probands with ciliary outer and inner dynein arm (ODA+IDA) defects. Mutations in SPAG1 were identified in one family with three affected siblings. Further screening of SPAG1 in 98 unrelated affected individuals (62 with ODA+IDA defects, 35 with ODA defects, 1 without available ciliary ultrastructure) revealed biallelic loss-of-function mutations in 11 additional individuals (including one sib-pair). All 14 affected individuals with SPAG1 mutations had a characteristic PCD phenotype, including 8 with situs abnormalities. Additionally, all individuals with mutations who had defined ciliary ultrastructure had ODA+IDA defects. SPAG1 was present in human airway epithelial cell lysates but was not present in isolated axonemes, and immunofluorescence staining showed an absence of ODA and IDA proteins in cilia from an affected individual, thus indicating that SPAG1 probably plays a role in the cytoplasmic assembly and/or trafficking of the axonemal dynein arms. Zebrafish morpholino studies of spag1 produced cilia-related phenotypes previously reported for PCD-causing mutations in genes encoding cytoplasmic proteins. Together, these results demonstrate that mutations in SPAG1 cause PCD with ciliary ODA+IDA defects and that exome sequencing is useful to identify genetic causes of heterogeneous recessive disorders.

AB - Primary ciliary dyskinesia (PCD) is a genetically heterogeneous, autosomal-recessive disorder, characterized by oto-sino-pulmonary disease and situs abnormalities. PCD-causing mutations have been identified in 20 genes, but collectively they account for only ∼65% of all PCDs. To identify mutations in additional genes that cause PCD, we performed exome sequencing on three unrelated probands with ciliary outer and inner dynein arm (ODA+IDA) defects. Mutations in SPAG1 were identified in one family with three affected siblings. Further screening of SPAG1 in 98 unrelated affected individuals (62 with ODA+IDA defects, 35 with ODA defects, 1 without available ciliary ultrastructure) revealed biallelic loss-of-function mutations in 11 additional individuals (including one sib-pair). All 14 affected individuals with SPAG1 mutations had a characteristic PCD phenotype, including 8 with situs abnormalities. Additionally, all individuals with mutations who had defined ciliary ultrastructure had ODA+IDA defects. SPAG1 was present in human airway epithelial cell lysates but was not present in isolated axonemes, and immunofluorescence staining showed an absence of ODA and IDA proteins in cilia from an affected individual, thus indicating that SPAG1 probably plays a role in the cytoplasmic assembly and/or trafficking of the axonemal dynein arms. Zebrafish morpholino studies of spag1 produced cilia-related phenotypes previously reported for PCD-causing mutations in genes encoding cytoplasmic proteins. Together, these results demonstrate that mutations in SPAG1 cause PCD with ciliary ODA+IDA defects and that exome sequencing is useful to identify genetic causes of heterogeneous recessive disorders.

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