Mutations in Dnaaf1 and Lrrc48 Cause Hydrocephalus, Laterality Defects, and Sinusitis in Mice.
We have previously described a forward genetic screen in mice for abnormalities of brain development. Characterization of two hydrocephalus mutants by whole-exome sequencing after whole-genome SNP mapping revealed novel recessive mutations in Dnaaf1 and Lrrc48 Mouse mutants of these two genes have not been previously reported. The Dnaaf1 mutant carries a mutation at the splice donor site of exon 4, which results in abnormal transcripts. The Lrrc48 mutation is a missense mutation at a highly conserved leucine residue, which is also associated with a decrease in Lrrc48 transcription. Both Dnaaf1 and Lrrc48 belong to a leucine-rich repeat-containing protein family and are components of the ciliary axoneme. Their Chlamydomonas orthologs are known to be required for normal ciliary beat frequency or flagellar waveform, respectively. Some Dnaaf1 or Lrrc48 homozygote mutants displayed laterality defects, suggesting a motile cilia defect in the embryonic node. Mucus accumulation and neutrophil infiltration in the maxillary sinuses suggested sinusitis. Dnaaf1 mutants showed postnatal lethality, and none survived to weaning age. Lrrc48 mutants survive to adulthood, but had male infertility. ARL13B immunostaining showed the presence of motile cilia in the mutants, and the distal distribution of DNAH9 in the axoneme of upper airway motile cilia appeared normal. The phenotypic abnormalities suggest that mutations in Dnaaf1 and Lrrc48 cause defects in motile cilia function.
Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute, Washington 98101 Division of Genetic Medicine, Department of Pediatrics, University of Washington Medical School, Seattle, Washington.
Seungshin
0000-0002-9498-4324
S
Ha
Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute, Washington 98101 Division of Genetic Medicine, Department of Pediatrics, University of Washington Medical School, Seattle, Washington.
Anna M
AM
Lindsay
Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute, Washington 98101 Division of Genetic Medicine, Department of Pediatrics, University of Washington Medical School, Seattle, Washington.
Andrew E
AE
Timms
Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute, Washington 98101 Division of Genetic Medicine, Department of Pediatrics, University of Washington Medical School, Seattle, Washington david.beier@seattlechildrens.org.
David R
0000-0002-0325-8520
DR
Beier
D000818:Animals; D000831:Animals, Newborn; D002923:Cilia / Q000235:genetics; D005260:Female; D007839:Functional Laterality / Q000235:genetics; D006849:Hydrocephalus / Q000235:genetics*; D007248:Infertility, Male / Q000235:genetics; D008297:Male; D008817:Mice, Mutant Strains; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D009154:Mutation; D012852:Sinusitis / Q000235:genetics*
C000625254:DNAAF1 protein, mouse; C000625253:LRRC48 protein, mouse; D008869:Microtubule-Associated Proteins
Dnaaf1/Lrrc50/Oda7; ENU mutagenesis; Lrrc48/FAP134/Drc3; motile cilia; primary ciliary dyskinesia