Expanding the phenotypic spectrum of <i>IFT81</i>: Associated ciliopathy syndrome

Ashraf, Tazeen; Vaina, Camelia Laura; Giri, Dinesh; Burren, Christine P; James, Margaret; Offiah, A.C.; Overton, Timothy G.; Baptista, Júlia; Ellard, Sian; Smithson, Sarah

doi:10.1002/ajmg.a.61781

Cited by 3 publications

(2 citation statements)

References 13 publications

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“…In total, 77 studies were excluded of which the following of interest: four studies with reason “surgical intervention unclear” as RA was solely mentioned in the study without describing surgical treatment. 2 16 17 18 Furthermore, three studies were excluded based on “different population” due to adult patient in one study 19 and data on RA not separately extractable from the ARM population in two studies. 20 21 Finally, one study was excluded with reason “other disease entity,” due to RA occurring after necrotizing enterocolitis (NEC), 22 and one study with reason “fetal intervention” due to RA correction in utero.…”

Section: Resultsmentioning

confidence: 99%

Outcomes after Surgical Treatment for Rectal Atresia in Children: Is There a Preferred Approach? A Systematic Review

et al. 2022

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Rectal atresia (RA) affects only 1 to 2% of all children with anorectal malformations. No consensus on optimal treatment strategy is yet achieved. Therefore, the aim of this systematic review is to summarize all surgical interventions for RA and outcomes described in the current literature. A literature search was conducted in PubMed, Embase, Web of Science, and Cochrane Library on January 24, 2022. All studies describing treatment for RA in children (< 18 years) were included. Operation technique and postoperative complications were listed. Only descriptive analysis was anticipated. Quality of the studies was assessed using Johanna Briggs Institute critical appraisal checklist for case reports and series. The search yielded 6,716 studies of which, after duplicate removal, 4,028 were excluded based on title and abstract screening. After full-text assessment, 22 of 90 studies were included, yielding 70 patients. Posterior sagittal anorectoplasty (PSARP) and pull-through were most performed (43/70 and 18/70 patients, respectively). Four patients experienced postoperative complications: anal stenosis (n = 1), anastomotic stenosis (n = 2), and death due to a pulmonary complication (n = 1). In the low-quality literature available, most patients with RA are treated with PSARP or pull-through technique. A low complication rate of both has been described but follow-up was often not mentioned. Larger well-designed studies should be performed to determine optimal treatment strategy for children with RA. This study reflects level of evidence V.

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Section: Resultsmentioning

confidence: 99%

Outcomes after Surgical Treatment for Rectal Atresia in Children: Is There a Preferred Approach? A Systematic Review

et al. 2022

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“…Primary ciliary dyskinesia has been associated with X-linked retinitis pigmentosa in patients carrying RPGR mutations ( 33 , 63 , 64 ). Situs inversus defects can occur in humans with IFT81 mutations and are found in mouse IFT-A mutants ( 65 , 66 ). Mutations in other IFT-B gene additional to IFT74 ( IFT81 , IFT20, IFT27, IFT172 ), and in IFT-A genes ( IFT140 ) can cause spermatogenesis defects and male infertility in mice ( 62 , 67–71 ).…”

Section: Discussionmentioning

confidence: 99%

Defective airway intraflagellar transport underlies a combined motile and primary ciliopathy syndrome caused by IFT74 mutations

Fassad

Rumman

Junger

et al. 2023

Human Molecular Genetics

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Ciliopathies are inherited disorders caused by defective cilia. Mutations affecting motile cilia usually cause the chronic muco-obstructive sinopulmonary disease primary ciliary dyskinesia (PCD) and are associated with laterality defects, while a broad spectrum of early developmental as well as degenerative syndromes arise from mutations affecting signalling of primary (non-motile) cilia. Cilia assembly and functioning requires intraflagellar transport of cargos assisted by IFT-B and IFT-A adaptor complexes. Within IFT-B, the N-termini of partner proteins IFT74 and IFT81 govern tubulin transport to build the ciliary microtubular cytoskeleton. We detected a homozygous 3 kb intragenic IFT74 deletion removing the exon 2 initiation codon and 40 N-terminal amino acids in two affected siblings. Both had clinical features of PCD with bronchiectasis, but no laterality defects. They also had retinal dysplasia and abnormal bone growth, with a narrowed thorax and short ribs, shortened long bones and digits and abnormal skull shape. This resembles short-rib thoracic dysplasia, a skeletal ciliopathy previously linked to IFT defects in primary cilia, not motile cilia. Ciliated nasal epithelial cells collected from affected individuals had reduced numbers of shortened motile cilia with disarranged microtubules, some mis-orientation of the basal feet, and disrupted cilia structural and IFT protein distributions. No full length IFT74 was expressed, only truncated forms that were consistent with N-terminal deletion and inframe translation from downstream initiation codons. In affinity purification mass spectrometry, exon 2-deleted IFT74 initiated from the nearest inframe downstream methionine 41 still interacts as part of the IFT-B complex, but only with reduced interaction levels and not with all its usual IFT-B partners. We propose that this is a hypomorphic mutation with some residual protein function retained, that gives rise to a non-lethal primary skeletal ciliopathy combined with defective motile cilia and PCD.

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Compound heterozygous IFT81 variations in a skeletal ciliopathy patient cause Bardet–Biedl syndrome-like ciliary defects

Tasaki

Zhou

Ishida

et al. 2023

Human Molecular Genetics

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Owing to their crucial roles in development and homeostasis, defects in cilia cause ciliopathies with diverse clinical manifestations. The intraflagellar transport (IFT) machinery, containing the IFT-A and IFT-B complexes, mediates not only the intraciliary bidirectional trafficking but also import and export of ciliary proteins together with the kinesin-2 and dynein-2 motor complexes. The BBSome, containing eight subunits encoded by causative genes of Bardet-Biedl syndrome (BBS), connects the IFT machinery to ciliary membrane proteins to mediate their export from cilia. Although mutations in subunits of the IFT-A and dynein-2 complexes cause skeletal ciliopathies, mutations in some IFT-B subunits are also known to cause skeletal ciliopathies. We here show that compound heterozygous variations of an IFT-B subunit, IFT81, found in a patient with skeletal ciliopathy cause defects in its interactions with other IFT-B subunits, and in ciliogenesis and ciliary protein trafficking when one of the two variants was expressed in IFT81-knockout (KO) cells. Notably, we found that IFT81-KO cells expressing IFT81 (Δ490-519), which lacks the binding site for the IFT25-IFT27 dimer, causes ciliary defects reminiscent of those found in BBS cells and those in IFT74-KO cells expressing a BBS variant of IFT74, which forms a heterodimer with IFT81. In addition, IFT81-KO cells expressing IFT81 (Δ490-519) in combination with the other variant, IFT81 (L645*), which mimics the cellular conditions of the above skeletal ciliopathy patient, demonstrated essentially the same phenotype as those expressing only IFT81 (Δ490-519). Thus, our data indicate that BBS-like defects can be caused by skeletal ciliopathy variants of IFT81.

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Expanding the phenotypic spectrum of IFT81: Associated ciliopathy syndrome

Cited by 3 publications

References 13 publications

Outcomes after Surgical Treatment for Rectal Atresia in Children: Is There a Preferred Approach? A Systematic Review

Outcomes after Surgical Treatment for Rectal Atresia in Children: Is There a Preferred Approach? A Systematic Review

Defective airway intraflagellar transport underlies a combined motile and primary ciliopathy syndrome caused by IFT74 mutations

Compound heterozygous IFT81 variations in a skeletal ciliopathy patient cause Bardet–Biedl syndrome-like ciliary defects

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