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Cold Spring Harb Mol Case Stud
2017 Jul 01;34:. doi: 10.1101/mcs.a001321.
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Compound heterozygous alterations in intraflagellar transport protein CLUAP1 in a child with a novel Joubert and oral-facial-digital overlap syndrome.
Johnston JJ
,
Lee C
,
Wentzensen IM
,
Parisi MA
,
Crenshaw MM
,
Sapp JC
,
Gross JM
,
Wallingford JB
,
Biesecker LG
.
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Disruption of normal ciliary function results in a range of diseases collectively referred to as ciliopathies. Here we report a child with a phenotype that overlapped with Joubert, oral-facial-digital, and Pallister-Hall syndromes including brain, limb, and craniofacial anomalies. We performed exome-sequence analysis on a proband and both parents, filtered for putative causative variants, and Sanger-verified variants of interest. Identified variants in CLUAP1 were functionally analyzed in a Xenopus system to determine their effect on ciliary function. Two variants in CLUAP1 were identified through exome-sequence analysis, Chr16:g.3558407T>G, c.338T>G, p.(Met113Arg) and Chr16:g.3570011C>T, c.688C>T, p.(Arg230Ter). These variants were rare in the Exome Aggregation Consortium (ExAC) data set of 65,000 individuals (one and two occurrences, respectively). Transfection of mutant CLUAP1 constructs into Xenopus embryos showed reduced protein levels p.(Arg230Ter) and reduced intraflagellar transport p.(Met113Arg). The genetic data show that these variants are present in an affected child, are rare in the population, and result in reduced, but not absent, intraflagellar transport. We conclude that biallelic mutations in CLUAP1 resulted in this novel ciliopathy syndrome in the proband.
Figure 1. Patient images showing (A) (via magnetic resonance imaging) the molar tooth sign; (B) the left hand showing postaxial polydactyly and partial cutaneous syndactyly of the fourth and fifth digits; (C) the left foot showing partial duplication of the hallux and partial cutaneous syndactyly of the second and third toes; (D) the right foot showing the broad hallux and nail; (E) (via radiograph) the right foot showing the duplicated distal phalanx of the hallux; and (F) the proband as an infant showing sparse scalp hair and eyebrows, epicanthal folds, wide nasal bridge and tip, and midline notch in the upper lip.
Figure 2. The CLUAP1 M113R mutant is expressed and localized normally, whereas the expression level of R230X mutants is extremely low. (AâF) Live images displaying localization of green fluorescent protein (GFP)-tagged CLUAP1 WT, M113R, and R230X proteins at the axonemes (AâC) and basal bodies (DâH) in Xenopus multiciliated cells. (Aâ²âCâ²) Merge views with membrane red fluorescent protein (RFP) visualizing axonemes. (Dâ²âFâ²) Merge views with cetn4-RFP, a basal body marker. Scale bars, 10 µm. (G) Western blotting of GFP-tagged CLUAP1 proteins. Actin was used as a loading control.
Figure 3. The CLUAP1 M113R mutant has significantly reduced intraflagellar transport (IFT) velocities. The graph shows velocities of green fluorescent protein (GFP)-tagged CLUAP1 wild type (WT) and M113R. Mean velocities ± SEM of CLUAP1 WT are 1.15 ± 0.05 µm/sec for anterograde (N = 33) and 1.25 ± 0.05 µm/sec for retrograde (N = 61). Mean velocities ± SEM of CLUAP1 M113R are 0.95 ± 0.05 µm/sec for anterograde (N = 42) and 1.14 ± 0.03 µm/sec for retrograde (N = 76). Comparing with WT, IFT velocities of M113R are significantly reduced (P value of WT vs. M113R is 0.0017 for anterograde and 0.0302 for retrograde).
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