Mutations in SPAG1 cause primary ciliary dyskinesia associated with defective outer and inner dynein arms.
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.
Department of Medicine, UNC School of Medicine, Chapel Hill, NC 27599, USA. Electronic address: knowles@med.unc.edu.
Michael R
MR
Knowles
Lawrence E
LE
Ostrowski
Niki T
NT
Loges
Toby
T
Hurd
Margaret W
MW
Leigh
Lu
L
Huang
Whitney E
WE
Wolf
Johnny L
JL
Carson
Milan J
MJ
Hazucha
Weining
W
Yin
Stephanie D
SD
Davis
Sharon D
SD
Dell
Thomas W
TW
Ferkol
Scott D
SD
Sagel
Kenneth N
KN
Olivier
Charlotte
C
Jahnke
Heike
H
Olbrich
Claudius
C
Werner
Johanna
J
Raidt
Julia
J
Wallmeier
Petra
P
Pennekamp
Gerard W
GW
Dougherty
Rim
R
Hjeij
Heon Yung
HY
Gee
Edgar A
EA
Otto
Jan
J
Halbritter
Moumita
M
Chaki
Katrina A
KA
Diaz
Daniela A
DA
Braun
Jonathan D
JD
Porath
Markus
M
Schueler
György
G
Baktai
Matthias
M
Griese
Emily H
EH
Turner
Alexandra P
AP
Lewis
Michael J
MJ
Bamshad
Deborah A
DA
Nickerson
Friedhelm
F
Hildebrandt
Jay
J
Shendure
Heymut
H
Omran
Maimoona A
MA
Zariwala
D000293:Adolescent; D000328:Adult; D000818:Animals; D000954:Antigens, Surface / Q000235:genetics*; D054468:Axoneme / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D002923:Cilia / Q000235:genetics*; D002925:Ciliary Motility Disorders / Q000235:genetics*; D003593:Cytoplasm / Q000235:genetics; D004398:Dyneins / Q000235:genetics*; D004847:Epithelial Cells / Q000378:metabolism; D059472:Exome; D005260:Female; D019204:GTP-Binding Proteins / Q000235:genetics*; D006801:Humans; D007223:Infant; D007619:Kartagener Syndrome / Q000235:genetics*; D008297:Male; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D055815:Young Adult; D015027:Zebrafish
D000954:Antigens, Surface; D019204:GTP-Binding Proteins; C483942:SPAG1 protein, human; D004398:Dyneins