Journal
HUMAN MOLECULAR GENETICS
Volume 27, Issue 3, Pages 529-545Publisher
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddx422
Keywords
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Funding
- British Heart Foundation [FS/13/32/30069]
- Sir Jules Thorn Award for Biomedical Research [JTA/09]
- Medical Research Council [MR/K011154/1, MR/M000532/1, MC_U142670370]
- Egyptian Government Scholarship
- European Community's Seventh Framework Programme FP7 [241955, 305608]
- Dutch Kidney Foundation KOUNCIL consortium [CP11.18]
- Medical Research Council Single Cell Grant [MR/M009084/1]
- Action Medical Research [GN2101]
- Great Ormond Street Hospital Children's Charity
- NIHR Great Ormond Street Hospital Biomedical Research Centre (GOSH BRC)
- Research Councils UK (RCUK)
- Charity Open Access Fund (COAF) to the University of Leeds
- BBSRC [BB/P007791/1, BB/M012522/1] Funding Source: UKRI
- MRC [MR/M009084/1, MR/K011154/1, MR/M000532/1, MC_U142670370] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/M012522/1, BB/P007791/1] Funding Source: researchfish
- British Heart Foundation [RG/15/14/31880, FS/13/32/30069] Funding Source: researchfish
- Great Ormond Street Hospital Childrens Charity [V2318, V4515] Funding Source: researchfish
- Medical Research Council [MC_U142670370, MR/M009084/1, MR/K011154/1, MR/M000532/1, 1774727] Funding Source: researchfish
- Rosetrees Trust [M279-F1] Funding Source: researchfish
- The Sir Jules Thorn Charitable Trust [09JTA] Funding Source: researchfish
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DNAAF1 (LRRC50) is a cytoplasmic protein required for dynein heavy chain assembly and cilia motility, and NAAF1 mutations cause primary ciliary dyskinesia (PCD; MIM 613193). We describe four families with DNAAF1 mutations and complex congenital heart disease (CHD). In three families, all affected individuals have typical PCD phenotypes. However, an additional family demonstrates isolated CHD (heterotaxy) in two affected siblings, but no clinical evidence of PCD. We identified a homozygous DNAAF1 missense mutation, p.Leu191Phe, as causative for heterotaxy in this family. Genetic complementation in dnaaf1-null zebrafish embryos demonstrated the rescue of normal heart looping with wild-type human DNAAF1, but not the p.Leu191Phe variant, supporting the conserved pathogenicity of this DNAAF1 missense mutation. This observation points to a phenotypic continuum between CHD and PCD, providing new insights into the pathogenesis of isolated CHD. In further investigations of the function of DNAAF1 in dynein arm assembly, we identified interactions with members of a putative dynein arm assembly complex. These include the ciliary intraflagellar transport protein IFT88 and the AAA+ (ATPases Associated with various cellular Activities) family proteins RUVBL1 (Pontin) and RUVBL2 (Reptin). Co-localization studies support these findings, with the loss of RUVBL1 perturbing the co-localization of DNAAF1 with IFT88. We show that RUVBL1 orthologues have an asymmetric left-sided distribution at both the mouse embryonic node and the Kupffer's vesicle in zebrafish embryos, with the latter asymmetry dependent on DNAAF1. These results suggest that DNAAF1-RUVBL1 biochemical and genetic interactions have a novel functional role in symmetry breaking and cardiac development.
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