The ophthalmic phenotype of<i>IFT140</i>-related ciliopathy ranges from isolated to syndromic congenital retinal dystrophy

Bifari, Inam N.; Elkhamary, Sahar; Bolz, Hanno J.; Khan, Arif O.

doi:10.1136/bjophthalmol-2015-307555

Cited by 24 publications

(26 citation statements)

References 12 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To explore additional cases of this duplication possibly missed by prior analysis, we retrospectively screened our cohorts and reanalyzed available high throughput sequencing panels including the IFT140 gene. As mutations in IFT140 are known to cause isolated to syndromic retinal degeneration (Bifari, Elkhamary, Bolz, & Khan, ), this included 126 patients using the Leber panel of the Imagine institute, 117 patients using the RP panel of Strasbourg Hospital, and 104 patients using the Ciliome panel of the Imagine institute (see section Materials and Methods and Supp. Materials and Methods).…”

Section: Resultsmentioning

confidence: 99%

“…). The most frequent mutation (31 alleles) is a missense (c.1990G > A, p.Glu664Lys) that has been observed in multiple studies and especially in 11 consanguineous families from the Arabian Peninsula sharing a common ancestor (Bifari, Elkhamary, Bolz, & Khan, ) which might bias the allele count. Nevertheless, the tandem duplication described in our study is the second most frequent cause of mutation in IFT140 representing 10 alleles.…”

Section: Discussionmentioning

confidence: 99%

“…Mainzer‐Saldino syndrome (MSS, MIM# 26692) is a rare (<1 out of 1,000,000) autosomal recessive ciliopathy characterized by severe early‐onset retinal dystrophy, phalangeal cone‐shaped epiphyses, chronic renal failure, and mild radiographic abnormality of the proximal femur (Perrault et al., ), known to be caused by IFT140 (Khan, Bolz, & Bergmann, ; Perrault et al., ; Schmidts et al., ) and IFT172 mutations (Halbritter et al., ). Both genes have been implicated in several other ciliopathies ranging from isolated retinis pigmentosa (RP) to more syndromic cases such as Jeune (JATD; MIM# 208500) or Bardet–Biedl syndromes (BBS; MIM# 209900) (Bifari, Elkhamary, Bolz, & Khan, ; Bujakowska et al., ; Schaefer et al., ).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Whole-genome sequencing in patients with ciliopathies uncovers a novel recurrent tandem duplication in IFT140

et al. 2018

View full text Add to dashboard Cite

Ciliopathies represent a wide spectrum of rare diseases with overlapping phenotypes and a high genetic heterogeneity. Among those, IFT140 is implicated in a variety of phenotypes ranging from isolated retinis pigmentosa to more syndromic cases. Using whole-genome sequencing in patients with uncharacterized ciliopathies, we identified a novel recurrent tandem duplication of exon 27-30 (6.7 kb) in IFT140, c.3454-488_4182+2588dup p.(Tyr1152_Thr1394dup), missed by whole-exome sequencing. Pathogenicity of the mutation was assessed on the patients' skin fibroblasts. Several hundreds of patients with a ciliopathy phenotype were screened and biallelic mutations were identified in 11 families representing 12 pathogenic variants of which seven are novel. Among those unrelated families especially with a Mainzer-Saldino syndrome, eight carried the same tandem duplication (two at the homozygous state and six at the heterozygous state). In conclusion, we demonstrated the implication of structural variations in IFT140-related diseases expanding its mutation spectrum. We also provide evidences for a unique genomic event mediated by an Alu-Alu recombination occurring on a shared haplotype. We confirm that whole-genome sequencing can be instrumental in the ability to detect structural variants for genomic disorders.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Whole-genome sequencing in patients with ciliopathies uncovers a novel recurrent tandem duplication in IFT140

et al. 2018

View full text Add to dashboard Cite

show abstract

“…Based on this observation, we predict that p.Gly212Arg retains at least partial function. This is supported by reports from IFT gene mutations in humans in which two loss of function mutations are likely incompatible with life past early embryogenesis; recessive null mutations are typically found in trans with hypomorphic changes [15–19, 23–27, 43–47, 57, 58]. However, further studies on the protein level will be required to determine whether p.Gly212Arg produces a stable and functional peptide.…”

Section: Discussionmentioning

confidence: 76%

“…This locus encodes a component of the retrograde intraflagellar transport complex [10]. Crucially, mutations in IFT140 cause a spectrum of ciliopathies, including MZSDS [24], JATD [24], syndromic and non-syndromic retinal dystrophy [43–45], Opitz trigonocephaly C syndrome [46], and Sensenbrenner syndrome [19]. To investigate the possibility that mutations in IFT140 could contribute to the proband’s clinical presentation, we conducted research-based Sanger sequencing of the 29 coding exons and intron-exon boundaries.…”

Section: Resultsmentioning

confidence: 99%

Partial uniparental isodisomy of chromosome 16 unmasks a deleterious biallelic mutation in IFT140 that causes Mainzer-Saldino syndrome

et al. 2017

View full text Add to dashboard Cite

BackgroundThe ciliopathies represent an umbrella group of >50 clinical entities that share both clinical features and molecular etiology underscored by structural and functional defects of the primary cilium. Despite the advances in gene discovery, this group of entities continues to pose a diagnostic challenge, in part due to significant genetic and phenotypic heterogeneity and variability. We consulted a pediatric case from asymptomatic, non-consanguineous parents who presented as a suspected ciliopathy due to a constellation of retinal, renal, and skeletal findings.ResultsAlthough clinical panel sequencing of genes implicated in nephrotic syndromes yielded no likely causal mutation, an oligo-SNP microarray identified a ~20-Mb region of homozygosity, with no altered gene dosage, on chromosome 16p13. Intersection of the proband’s phenotypes with known disease genes within the homozygous region yielded a single candidate, IFT140, encoding a retrograde intraflagellar transport protein implicated previously in several ciliopathies, including the phenotypically overlapping Mainzer-Saldino syndrome (MZSDS). Sanger sequencing yielded a maternally inherited homozygous c.634G>A; p.Gly212Arg mutation altering the exon 6 splice donor site. Functional studies in cells from the proband showed that the locus produced two transcripts: a majority message containing a mis-splicing event that caused a premature termination codon and a minority message homozygous for the p.Gly212Arg allele. Zebrafish in vivo complementation studies of the latter transcript demonstrated a loss of function effect. Finally, we conducted post-hoc trio-based whole exome sequencing studies to (a) test the possibility of other causal loci in the proband and (b) explain the Mendelian error of segregation for the IFT140 mutation. We show that the proband harbors a chromosome 16 maternal heterodisomy, with segmental isodisomy at 16p13, likely due to a meiosis I error in the maternal gamete.ConclusionsUsing clinical phenotyping combined with research-based genetic and functional studies, we have characterized a recurrent IFT140 mutation in the proband; together, these data are consistent with MZSDS. Additionally, we report a rare instance of a uniparental isodisomy unmasking a deleterious mutation to cause a ciliary disorder.Electronic supplementary materialThe online version of this article (doi:10.1186/s40246-017-0111-9) contains supplementary material, which is available to authorized users.

show abstract

Intraflagellar transport: A critical player in photoreceptor development and the pathogenesis of retinal degenerative diseases

Gupta,

Pazour

2023

Cytoskeleton

View full text Add to dashboard Cite

In vertebrate vision, photons are detected by highly specialized sensory cilia called outer segments. Photoreceptor outer segments form by remodeling the membrane of a primary cilium into a stack of flattened disks. Intraflagellar transport (IFT) is critical to the formation of most types of eukaryotic cilia including the outer segments. This review covers the state of knowledge of the role of IFT in the formation and maintenance of outer segments and the human diseases that result from mutations in genes encoding the IFT complex and associated motors.

show abstract

The ophthalmic phenotype ofIFT140-related ciliopathy ranges from isolated to syndromic congenital retinal dystrophy

Cited by 24 publications

References 12 publications

Whole-genome sequencing in patients with ciliopathies uncovers a novel recurrent tandem duplication in IFT140

Whole-genome sequencing in patients with ciliopathies uncovers a novel recurrent tandem duplication in IFT140

Partial uniparental isodisomy of chromosome 16 unmasks a deleterious biallelic mutation in IFT140 that causes Mainzer-Saldino syndrome

Intraflagellar transport: A critical player in photoreceptor development and the pathogenesis of retinal degenerative diseases

Contact Info

Product

Resources

About