Sensenbrenner syndrome (Cranioectodermal dysplasia): Clinical and molecular analyses of 39 patients including two new patients

Lin, Angela E.; Traum, Avram Z.; Sahai, Inderneel; Keppler‐Noreuil, Kim M.; Kukolich, Mary K.; Adam, Margaret P; Westra, Sjirk J.; Arts, Heleen H.

doi:10.1002/ajmg.a.36265

Cited by 59 publications

(58 citation statements)

References 36 publications

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“…Mutations in Wdr35 are linked to multiple recessive developmental diseases, including short-rib polydactyly as well as Sensenbrenner and Ellis-van Creveld syndromes (Bacino et al, 2012; Caparros-Martin et al, 2015; Gilissen et al, 2010; Hoffer et al, 2013; Lin et al, 2013; Mill et al, 2011). To test how such mutations could affect a Wdr35-dependent transport pathway, we expressed epitope-tagged Wdr35 disease-related and truncation mutants (all mutants analyzed, except fragments encompassing residues 641–1181 and 337–1181, are associated with disease) in an effort to rescue the defects observed in WDR35 KO cells (Figures 6A-6D, S7A and S7B).…”

Section: Resultsmentioning

confidence: 99%

Role for the IFT-A Complex in Selective Transport to the Primary Cilium

Fu¹,

Wang²,

Kim³

et al. 2016

Cell Reports

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Summary Intraflagellar transport sub-complex A (IFT-A) is known to regulate retrograde IFT in the cilium. To rigorously assess its other possible roles, we knocked out an IFT-A subunit, IFT121/WDR35, in mammalian cells and screened the localization of more than 50 proteins. We found that Wdr35 regulates cilium assembly by selectively regulating transport of distinct cargoes. Beyond its role in retrograde transport, we show that Wdr35 functions in fusion of Rab8 vesicles at the nascent cilium, protein exit from the cilium, and centriolar satellite organization. Further, we show that Wdr35 is essential for entry of many membrane proteins into the cilium through robust interactions with cargoes and other IFT-A subunits, but the actin network functions to dampen this transport. Wdr35 is mutated in several ciliopathies, and we find that certain disease mutations impair interactions with cargo and other IFT-A subunits. Together, our data link defects in IFT-A mediated cargo transport with disease.

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Section: Resultsmentioning

confidence: 99%

Role for the IFT-A Complex in Selective Transport to the Primary Cilium

Fu¹,

Wang²,

Kim³

et al. 2016

Cell Reports

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“…Diagnosis of Sensenbrenner is typically based on clinical examination, ultrasound (renal and liver), laboratory studies (ie, urine analysis, serum electrolytes, liver panel, and lipid profile), histologic examination of the liver and kidney, and clinical genetics consultation. Renal and liver diseases are the major contributors of morbidity and complications of rapid renal deterioration are the most common causes of death for patients with Sensenbrenner …”

Section: Discussionmentioning

confidence: 99%

“…For all Sensenbrenner patients, renal and liver diseases are the main contributors of morbidity and mortality. Liver involvement has been noted in 40%‐50% of patients with Sensenbrenner syndrome, regardless of mutation status . Findings vary from hepatosplenomegaly in the absence of progressive liver disease to extensive liver abnormalities including recurrent hyperbilirubinemia, severe cholestatic disease with bile ductal proliferation, sometimes manifested by acute cholangitis in the neonatal period .…”

Section: Introductionmentioning

confidence: 99%

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Orthotopic liver transplantation for Sensenbrenner syndrome

Ackah

Yoeli

Kueht

et al. 2017

Pediatric Transplantation

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Sensenbrenner syndrome, or cranioectodermal dysplasia, is a rare heterogeneic autosomal recessive disorder, affecting ~1 of 1 000 000 live births. The syndrome usually manifests within the first year of life and can present with progressive liver and renal involvement. For all Sensenbrenner patients, renal and liver diseases are the main contributors of morbidity and mortality. In this report, we present the case of a 7-year-old boy with congenital liver disease progressing to liver failure secondary to Sensenbrenner syndrome. For this patient, evidence of liver dysfunction was evident from 2 months of age and progressed to frank cirrhosis and severe portal hypertension with multiple episodes of life-threatening variceal bleeding by age 6. This report illustrates the capability of orthotopic liver transplantation as a viable therapy for those pediatric patients suffering from severe liver failure secondary to a congenital ciliopathy, such as Sensenbrenner syndrome. In fact, early emphasis should be placed on the renal and liver involvement associated with Sensenbrenner syndrome with particular consideration for early referral for transplantation in cases with severe disease. Although the condition is rare, clinicians should be aware of it and its association with fatal liver disease to facilitate appropriate evaluation and referral.

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“…The major distinguishing feature of Sensenbrenner syndrome is the presence of ectodermal defects, including sparse hair, missing teeth, and nail anomalies. Most Sensenbrenner patients display a distinctive facial appearance with forehead bossing, high hairline, and dolichocephaly (disproportionately long narrow head) often associated with craniosynostosis, and in some cases a high arched palate …”

Section: Function Of Ciliopathy Proteins Leading To Craniofacial Defectsmentioning

confidence: 99%

Unmasking the ciliopathies: craniofacial defects and the primary cilium

Cortés

Metzis

Wicking

2015

WIREs Developmental Biology

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Over the past decade, the primary cilium has emerged as a pivotal sensory organelle that acts as a major signaling hub for a number of developmental signaling pathways. In that time, a vast number of proteins involved in trafficking and signaling have been linked to ciliary assembly and/or function, demonstrating the importance of this organelle during embryonic development. Given the central role of the primary cilium in regulating developmental signaling, it is not surprising that its dysfunction results in widespread defects in the embryo, leading to an expanding class of human congenital disorders known as ciliopathies. These disorders are individually rare and phenotypically variable, but together they affect virtually every vertebrate organ system. Features of ciliopathies that are often overlooked, but which are being reported with increasing frequency, are craniofacial abnormalities, ranging from subtle midline defects to full-blown orofacial clefting. The challenge moving forward is to understand the primary mechanism of disease given the link between the primary cilium and a number of developmental signaling pathways (such as hedgehog, platelet-derived growth factor, and WNT signaling) that are essential for craniofacial development. Here, we provide an overview of the diversity of craniofacial abnormalities present in the ciliopathy spectrum, and reveal those defects in common across multiple disorders. Further, we discuss the molecular defects and potential signaling perturbations underlying these anomalies. This provides insight into the mechanisms leading to ciliopathy phenotypes more generally and highlights the prevalence of widespread dysmorphologies resulting from cilia dysfunction.

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Sensenbrenner syndrome (Cranioectodermal dysplasia): Clinical and molecular analyses of 39 patients including two new patients

Cited by 59 publications

References 36 publications

Role for the IFT-A Complex in Selective Transport to the Primary Cilium

Role for the IFT-A Complex in Selective Transport to the Primary Cilium

Orthotopic liver transplantation for Sensenbrenner syndrome

Unmasking the ciliopathies: craniofacial defects and the primary cilium

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