Mainzer-Saldino Syndrome Is a Ciliopathy Caused by IFT140 Mutations

Perrault, Isabelle; Saunier, Sophie; Hanein, Sylvain; Filhol, Emilie; Bizet, Albane A.; Collins, Felicity; Salih, Mustafa A.; Gerber, Sylvie; Delphin, Nathalie; Bigot, Karine; Orssaud, C.; Silva, Eduardo D.; Baudouin, Véronique; Oud, Machteld M.; Shannon, Nora; Merrer, Martine Le; Roche, Olivier; Piètrement, Christine; Goumid, Jamal; Baumann, Clarisse; Bôle‐Feysot, Christine; Nitschké, Patrick; Zahrate, Mohammed; Beales, Philip L.; Arts, Heleen H.; Münnich, Arnold; Kaplan, Josseline; Antignac, Corinne; Cormier‐Daire, Valérie; Rozet, Jean–Michel

doi:10.1016/j.ajhg.2012.03.006

Cited by 181 publications

(214 citation statements)

References 25 publications

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“…These features overlap with those of Mainzer Saldino syndrome (caused by IFT140 or IFT172 mutations), which includes early-onset severe retinal dystrophy. 18,19 Spondylometaphyseal dysplasias with cone-rod dystrophy (caused by PCYT1A mutations) was another differential diagnosis, but the index in 13DG0374 lacked the typical platyspondyly with anterior vertebral protrusions and progressive metaphyseal irregularity and cupping typical of that disorder. 20 Several families had other unusual syndromic associations, e.g., a family with LCA, neuroregression, and intractable seizures; one with retinitis pigmentosa and skeletal dysplasia; and another with retinitis pigmentosa, tufting enteropathy, and microcephaly ( Table 2).…”

Section: Clinical Profilementioning

confidence: 99%

Expanding the clinical, allelic, and locus heterogeneity of retinal dystrophies

Patel

Aldahmesh

Alkuraya

et al. 2016

Genetics in Medicine

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Purpose:Retinal dystrophies (RD) are heterogeneous hereditary disorders of the retina that are usually progressive in nature. The aim of this study was to clinically and molecularly characterize a large cohort of RD patients. Methods:We have developed a next-generation sequencing assay that allows known RD genes to be sequenced simultaneously. We also performed mapping studies and exome sequencing on familial and on syndromic RD patients who tested negative on the panel. Results:Our panel identified the likely causal mutation in >60% of the 292 RD families tested. Mapping studies on all 162 familial RD patients who tested negative on the panel identified two novel disease loci on Chr2:25,550,180-28,794,007 and Chr16:59,225,000-72,511,000. Whole-exome sequencing revealed the likely candidate as AGBL5 and CDH16, respectively. We also performed exome sequencing on negative syndromic RD cases and identified a novel homozygous truncating mutation in GNS in a family with the novel combination of mucopolysaccharidosis and RD. Moreover, we identified a homozygous truncating mutation in DNAJC17 in a family with an apparently novel syndrome of retinitis pigmentosa and hypogammaglobulinemia. Conclusion:Our study expands the clinical and allelic spectrum of known RD genes, and reveals AGBL5, CDH16, and DNAJC17 as novel disease candidates.

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Section: Clinical Profilementioning

confidence: 99%

Expanding the clinical, allelic, and locus heterogeneity of retinal dystrophies

Patel

Aldahmesh

Alkuraya

et al. 2016

Genetics in Medicine

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“…The IFT complexes transport proteins that are necessary for the assembly and maintenance of cilia (Ishikawa and Marshall, 2011), and also move signals between the cilium and cell body (Eguether et al, 2014;Liem et al, 2012;Liew et al, 2014;Wang et al, 2006). Mutations in IFT motors and complex proteins cause defects in ciliary assembly and function, resulting in several human diseases, including Jeune asphyxiating thoracic dystrophy, short-rib polydactyly syndrome, Mainzer-Saldino syndrome and Ellis-van Creveld syndrome (Aldahmesh et al, 2014;Beales et al, 2007;Caparrós-Martín et al, 2015;Dagoneau et al, 2009;Davis et al, 2011;Halbritter et al, 2013;Huber et al, 2013;McInerney-Leo et al, 2013;Merrill et al, 2009;Perrault et al, 2012Perrault et al, , 2015Schmidts et al, 2013Schmidts et al, , 2015.…”

Section: Introductionmentioning

confidence: 99%

Together, the IFT81 and IFT74 N-termini form the main module for intraflagellar transport of tubulin

Kubo

Brown

Bellvé

et al. 2016

Journal of Cell Science

102

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The assembly and maintenance of most cilia and flagella rely on intraflagellar transport (IFT). Recent in vitro studies have suggested that, together, the calponin-homology domain within the IFT81 N-terminus and the highly basic N-terminus of IFT74 form a module for IFT of tubulin. By using Chlamydomonas mutants for IFT81 and IFT74, we tested this hypothesis in vivo. Modification of the predicted tubulin-binding residues in IFT81 did not significantly affect basic anterograde IFT and length of steady-state flagella but slowed down flagellar regeneration, a phenotype similar to that seen in a strain that lacks the IFT74 N-terminus. In both mutants, the frequency of tubulin transport by IFT was greatly reduced. A double mutant that combined the modifications to IFT81 and IFT74 was able to form only very short flagella. These results indicate that, together, the IFT81 and IFT74 N-termini are crucial for flagellar assembly, and are likely to function as the main module for IFT of tubulin.

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“…125 IFT140 is essential for normal photoreceptor development in humans. Mutations in human IFT140 are a cause of Mainzer-Saldino syndrome (MZSDS) 131 and ATD, 132 both of which are skeletal ciliopathies that are associated with retinal dystrophy phenotypes. TTC21B, another IFT complex A protein, also localizes to the photoreceptor axoneme, and loss of this protein in mutant mice leads to defective photoreceptor development.…”

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confidence: 99%