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A novel ICK mutation causes ciliary disruption and lethal endocrine-cerebro-osteodysplasia syndrome.Cilia 2016Endocrine-cerebro-osteodysplasia (ECO) syndrome [MIM:612651] caused by a recessive mutation (p.R272Q) in Intestinal cell kinase (ICK) shows significant clinical overlap...
BACKGROUND
Endocrine-cerebro-osteodysplasia (ECO) syndrome [MIM:612651] caused by a recessive mutation (p.R272Q) in Intestinal cell kinase (ICK) shows significant clinical overlap with ciliary disorders. Similarities are strongest between ECO syndrome, the Majewski and Mohr-Majewski short-rib thoracic dysplasia (SRTD) with polydactyly syndromes, and hydrolethalus syndrome. In this study, we present a novel homozygous ICK mutation in a fetus with ECO syndrome and compare the effect of this mutation with the previously reported ICK variant on ciliogenesis and cilium morphology.
RESULTS
Through homozygosity mapping and whole-exome sequencing, we identified a second variant (c.358G > T; p.G120C) in ICK in a Turkish fetus presenting with ECO syndrome. In vitro studies of wild-type and mutant mRFP-ICK (p.G120C and p.R272Q) revealed that, in contrast to the wild-type protein that localizes along the ciliary axoneme and/or is present in the ciliary base, mutant proteins rather enrich in the ciliary tip. In addition, immunocytochemistry revealed a decreased number of cilia in ICK p.R272Q-affected cells.
CONCLUSIONS
Through identification of a novel ICK mutation, we confirm that disruption of ICK causes ECO syndrome, which clinically overlaps with the spectrum of ciliopathies. Expression of ICK-mutated proteins result in an abnormal ciliary localization compared to wild-type protein. Primary fibroblasts derived from an individual with ECO syndrome display ciliogenesis defects. In aggregate, our findings are consistent with recent reports that show that ICK regulates ciliary biology in vitro and in mice, confirming that ECO syndrome is a severe ciliopathy.
PubMed: 27069622
DOI: 10.1186/s13630-016-0029-1 -
American Journal of Medical Genetics.... Jan 2017The Peter the Great Museum of Anthropology and Ethnography (Kunstkamera) in Saint Petersburg is the oldest museum in Russia. It keeps the remains of the anatomical... (Review)
Review
The Peter the Great Museum of Anthropology and Ethnography (Kunstkamera) in Saint Petersburg is the oldest museum in Russia. It keeps the remains of the anatomical collection of the world-famous 17th century Dutch anatomist Frederik Ruysch. This unique collection was bought and shipped in 1717 by Czar Peter the Great, and presently still comprises more than 900 specimens, a modest number of which concerns specimens with congenital anomalies. We searched for teratological clues in the existing collection and in all his descriptions and correspondence regarding specimens and cases he encountered during his career as doctor anatomiae and chief instructor of the surgeons and midwives in Amsterdam. A total of 63 teratological specimens and case descriptions were identified in this legacy, including some exceedingly rare anomalies. As it turns out, Ruysch was the first to describe several of the conditions we encountered, including intracranial teratoma, enchondromatosis, and Majewski syndrome. Although his comments pose an interesting view on how congenital anomalies were scientifically perceived in early 18th century Europe, Ruysch mostly refrained from explaining the causes of the conditions he encountered. Instead, he dedicated himself to careful descriptions of his specimens. Almost 300 years after his demise, Ruysch's legacy still impresses and inspires both scientists and lay men. © 2016 The Authors. American Journal of Medical Genetics Part A Published by Wiley Periodicals, Inc.
Topics: Anatomy; Biological Specimen Banks; Congenital Abnormalities; Famous Persons; History, 17th Century; History, 18th Century; Humans; Museums; Myxoma; Netherlands; Russia; Teratoma; Twins, Conjoined
PubMed: 27126916
DOI: 10.1002/ajmg.a.37663 -
Journal of Rare Diseases Research &... 2016Lenz-Majewski syndrome (LMS) is a rare disease presenting with complex physical and mental abnormalities. Whole exome sequencing performed on five LMS-affected...
Lenz-Majewski syndrome (LMS) is a rare disease presenting with complex physical and mental abnormalities. Whole exome sequencing performed on five LMS-affected individuals has identified gain-of-function mutations in the PTDSS1 gene encoding phosphatidylserine synthase 1 (PSS1) enzyme. These mutations all rendered PSS1 insensitive to PS-mediated product inhibition. In a recent study we showed that uncontrolled PS production by these mutant PSS1 enzymes lead to the accumulation of PS in the ER where it is not detected in normal cells. This increased PS in the ER in turn, activated the Sac1 phosphatase, which is responsible for the dephosphorylation of the minor lipid, phosphatidylinositol 4-phosphate (PI4P) in the ER. Increased Sac1 activity decreased PI4P levels both in the Golgi and the plasma membrane thereby dissipating the PI4P gradients set up by PI 4-kinase enzymes (PI4Ks) between these membranes and the ER. Such PI4P gradients at membrane contact sites have been shown to support the transports of structural lipids such as cholesterol and PS out of the ER by non-vesicular lipid transfer. Therefore, uncontrolled production of PS not only affects the PS status of cells but also initiates an avalanche of changes in the metabolism of other membrane lipids via affecting PI4P gradients throughout the cell. Recognition of the close metabolic interaction between PS synthesis and PI4P metabolism provided a new clue to better understand the molecular underpinning of this rare and severe disease.
PubMed: 30854527
DOI: 10.29245/2572-9411/2017/1.1080 -
Congenital Anomalies Nov 2014The Majewski syndrome or short rib-polydactyly syndrome (SRPS) type II is a lethal skeletal dysplasia characterized by severe IUGR (intrauterine growth restriction) and...
The Majewski syndrome or short rib-polydactyly syndrome (SRPS) type II is a lethal skeletal dysplasia characterized by severe IUGR (intrauterine growth restriction) and dysmorphic face, polydactyly, relatively proportionate head size at birth with later progression to microcephaly. A case of second trimester ultrasound diagnosis of SRPS type II is reported with review of the medical record of previous observed cases. Postmortem examination and radiogram confirmed the clinical diagnosis. Histological examination of the femoral epypheseal chondral plate showed an expanded and irregular hypertrophic zone. Moreover, characteristic cortico-medullary cysts of both kidneys and portal fibrosis were also demonstrated; findings consistent with the broad phenotypic spectrum of this rare skeletal disease.
Topics: Adult; Female; Growth Plate; Humans; Kidney; Liver; Pregnancy; Prenatal Diagnosis; Short Rib-Polydactyly Syndrome; Ultrasonography, Prenatal
PubMed: 24854045
DOI: 10.1111/cga.12066 -
Frontiers in Genetics 2022Ciliopathies are rare congenital disorders, caused by defects in the cilium, that cover a broad clinical spectrum. A subgroup of ciliopathies showing significant...
Ciliopathies are rare congenital disorders, caused by defects in the cilium, that cover a broad clinical spectrum. A subgroup of ciliopathies showing significant phenotypic overlap are known as skeletal ciliopathies and include Jeune asphyxiating thoracic dysplasia (JATD), Mainzer-Saldino syndrome (MZSDS), cranioectodermal dysplasia (CED), and short-rib polydactyly (SRP). Ciliopathies are heterogeneous disorders with >187 associated genes, of which some genes are described to cause more than one ciliopathy phenotype. Both the clinical and molecular overlap make accurate diagnosing of these disorders challenging. We describe two unrelated Polish patients presenting with a skeletal ciliopathy who share the same compound heterozygous variants in (NM_014,714.4) r.2765_2768del; p.(Tyr923Leufs*28) and exon 27-30 duplication; p.(Tyr1152_Thr1394dup). Apart from overlapping clinical symptoms the patients also show phenotypic differences; patient 1 showed more resemblance to a Mainzer-Saldino syndrome (MZSDS) phenotype, while patient 2 was more similar to the phenotype of cranioectodermal dysplasia (CED). In addition, functional testing in patient-derived fibroblasts revealed a distinct cilium phenotyps for each patient, and strikingly, the cilium phenotype of CED-like patient 2 resembled that of known CED patients. Besides two variants in , in depth exome analysis of ciliopathy associated genes revealed a likely-pathogenic heterozygous variant in for patient 2 that possibly affects the same IFT-A complex to which IFT140 belongs and thereby could add to the phenotype of patient 2. Taken together, by combining genetic data, functional test results, and clinical findings we were able to accurately diagnose patient 1 with "IFT140-related ciliopathy with MZSDS-like features" and patient 2 with "IFT140-related ciliopathy with CED-like features". This study emphasizes that identical variants in one ciliopathy associated gene can lead to a variable ciliopathy phenotype and that an in depth and integrated analysis of clinical, molecular and functional data is necessary to accurately diagnose ciliopathy patients.
PubMed: 35873489
DOI: 10.3389/fgene.2022.931822 -
Journal of Pediatric Genetics Nov 2014Ciliary chondrodysplasias represent a heterogenous group of rare, nearly exclusively autosomal recessively inherited developmental conditions. While the skeletal...
Ciliary chondrodysplasias represent a heterogenous group of rare, nearly exclusively autosomal recessively inherited developmental conditions. While the skeletal phenotype, mainly affecting limbs, ribs and sometimes the craniofacial skeleton, is predominant, extraskeletal disease affecting the kidneys, liver, heart, eyes and other organs and tissues is observed inconsistently. Significant lethality, resulting from cardiorespiratory failure due to thoracic constriction as well as from renal and hepatic insufficiency or primary cardiac failure due to congenital heart disease, is observed with these conditions. The underlying genetic defects as well as developmental biology and cell biology work undertaken using animal model systems, suggest that these rare conditions result from ciliary malfunction. The skeletal phenotype is believed to result from imbalances in the hedgehog signaling pathway that normally occurs in functional cilia in chondrocytes. Although phenotypes have been historically distinguished based on clinical features into short-rib polydactyly syndrome, Jeune asphyxiating thoracic dystrophy, Mainzer-Saldino syndrome, Sensenbrenner syndrome (cranioectodermal dysplasia), oral-facial-digital syndrome and Ellis-van Creveld syndrome, recent research suggests that there is significant genetic as well as phenotypic overlap between the conditions. This review discusses ciliary chondrodysplasias from phenotypic hallmarks to clinical management and summarizes progress in identification of the underlying molecular mechanisms as well as potential future therapeutic perspectives.
PubMed: 25506500
DOI: 10.3233/PGE-14089 -
Molecular Biology of the Cell Aug 2022Bidirectional protein trafficking within cilia is mediated by the intraflagellar transport (IFT) machinery, which contains the IFT-A and IFT-B complexes powered by the...
Bidirectional protein trafficking within cilia is mediated by the intraflagellar transport (IFT) machinery, which contains the IFT-A and IFT-B complexes powered by the kinesin-2 and dynein-2 motors. Mutations in genes encoding subunits of the IFT-A and dynein-2 complexes cause skeletal ciliopathies. Some subunits of the IFT-B complex, including IFT52, IFT80, and IFT172, are also mutated in skeletal ciliopathies. We here show that IFT52 variants found in individuals with short-rib polydactyly syndrome (SRPS) are compromised in terms of formation of the IFT-B holocomplex from two subcomplexes and its interaction with heterotrimeric kinesin-II. -knockout (KO) cells expressing IFT52 variants that mimic the cellular conditions of individuals with SRPS demonstrated mild ciliogenesis defects and a decrease in ciliary IFT-B level. Furthermore, in -KO cells expressing an SRPS variant of IFT52, ciliary tip localization of ICK/CILK1 and KIF17, both of which are likely to be transported to the tip via binding to the IFT-B complex, was significantly impaired. Altogether these results indicate that impaired anterograde trafficking caused by a decrease in the ciliary level of IFT-B or in its binding to kinesin-II underlies the ciliary defects found in skeletal ciliopathies caused by IFT52 variations.
Topics: Adaptor Proteins, Signal Transducing; Cilia; Ciliopathies; Cytoskeletal Proteins; Dyneins; Flagella; Humans; Mutation; Protein Transport
PubMed: 35704471
DOI: 10.1091/mbc.E22-05-0188 -
Human Molecular Genetics Oct 2018Skeletal dysplasias are a clinically and genetically heterogeneous group of bone and cartilage disorders. A total of 436 skeletal dysplasias are listed in the 2015...
Skeletal dysplasias are a clinically and genetically heterogeneous group of bone and cartilage disorders. A total of 436 skeletal dysplasias are listed in the 2015 revised version of the nosology and classification of genetic skeletal disorders, of which nearly 20% are still genetically and molecularly uncharacterized. We report the clinical and molecular characterization of a lethal skeletal dysplasia of the short-rib group caused by mutation of the mouse Fop gene. Fop encodes a centrosomal and centriolar satellite (CS) protein. We show that Fop mutation perturbs ciliogenesis in vivo and that this leads to the alteration of the Hedgehog signaling pathway. Fop mutation reduces CSs movements and affects pericentriolar material composition, which probably participates to the ciliogenesis defect. This study highlights the role of a centrosome and CSs protein producing phenotypes in mice that recapitulate a short rib-polydactyly syndrome when mutated.
Topics: Animals; Centrioles; Centrosome; Cilia; Ciliopathies; Humans; Mice; Mutation; Proto-Oncogene Proteins; Short Rib-Polydactyly Syndrome; Transcription Factors
PubMed: 29982567
DOI: 10.1093/hmg/ddy246 -
Proceedings of the National Academy of... Apr 2016Lenz-Majewski syndrome (LMS) is a rare disease characterized by complex craniofacial, dental, cutaneous, and limb abnormalities combined with intellectual disability....
Lenz-Majewski syndrome (LMS) is a rare disease characterized by complex craniofacial, dental, cutaneous, and limb abnormalities combined with intellectual disability. Mutations in thePTDSS1gene coding one of the phosphatidylserine (PS) synthase enzymes, PSS1, were described as causative in LMS patients. Such mutations render PSS1 insensitive to feedback inhibition by PS levels. Here we show that expression of mutant PSS1 enzymes decreased phosphatidylinositol 4-phosphate (PI4P) levels both in the Golgi and the plasma membrane (PM) by activating the Sac1 phosphatase and altered PI4P cycling at the PM. Conversely, inhibitors of PI4KA, the enzyme that makes PI4P in the PM, blocked PS synthesis and reduced PS levels by 50% in normal cells. However, mutant PSS1 enzymes alleviated the PI4P dependence of PS synthesis. Oxysterol-binding protein-related protein 8, which was recently identified as a PI4P-PS exchanger between the ER and PM, showed PI4P-dependent membrane association that was significantly decreased by expression of PSS1 mutant enzymes. Our studies reveal that PS synthesis is tightly coupled to PI4P-dependent PS transport from the ER. Consequently, PSS1 mutations not only affect cellular PS levels and distribution but also lead to a more complex imbalance in lipid homeostasis by disturbing PI4P metabolism.
Topics: Abnormalities, Multiple; Bone Diseases, Developmental; Cell Membrane; Endoplasmic Reticulum; Golgi Apparatus; HEK293 Cells; Humans; Intellectual Disability; Minor Histocompatibility Antigens; Mutation; Nitrogenous Group Transferases; Phosphatidylinositol Phosphates; Phosphotransferases (Alcohol Group Acceptor)
PubMed: 27044099
DOI: 10.1073/pnas.1525719113 -
Gene May 2019Autosomal recessive disorder is closely correlated with congenital fetal malformation. The mutation of WDR35 may lead to short rib-polydactyly syndrome (SRP),...
BACKGROUND
Autosomal recessive disorder is closely correlated with congenital fetal malformation. The mutation of WDR35 may lead to short rib-polydactyly syndrome (SRP), asphyxiating thoracic dystrophy (ATD, Jeune syndrome) and Ellis van Creveld syndrome. The purpose of this study is to investigate the role of WDR35 in fetal anomaly.
RESULTS
The fetuses presented malformation with abnormal head shape, cardiac dilatation, pericardial effusion, and non-displayed left pulmonary artery and left lung. After the detection of genomic DNA (gDNA) in amniotic fluid cells (AFC), chromosomal rearrangement was found in arr[hg19] 2p25.3p23.3. It was revealed through multiple PCR-DHPLC that MYCN, WDR35, LPIN1, ODC1, KLF11 and NBAS contained duplicated copy numbers in 2p25.3p23.3. AF-MSCs were mostly positive for CD44, CD105, negative for CD34 and CD14. Western Blot test showed that WDR35-encoded protein was decreased in the patients' AFC compared to that in normal pregnant women. In the patients' amniotic fluid-derived mesenchymal stem cells (AF-MSCs), WDR35 overexpression could repair cilia formation, and the overexpression of WDR35 or Gli2 could significantly enhance ALP activity and expressions of osteogenic differentiation marker genes, including RUNXE2, OCN, BSP and ALP. However, WDR35 silencing in C3H10T1/2 cells could remarkably inhibit cilia formation and osteogenic differentiation. This inhibitory effect could be attenuated by Gli2 overexpression.
CONCLUSIONS
The results demonstrated that copy number variation (CNV) of WDR35 may lead to skeletal dysplasia and fetal anomaly, and that down-regulated WDR35 may damage the cilia formation and sequentially indirectly regulate Gli signal, which would eventually result in negative regulation of osteogenic differentiation.
Topics: Adult; Amniotic Fluid; Animals; Bone Diseases, Developmental; Cell Differentiation; Cilia; Cytoskeletal Proteins; DNA Copy Number Variations; Female; Fetal Development; Hedgehog Proteins; Humans; Intracellular Signaling Peptides and Proteins; Mesenchymal Stem Cells; Mice; Mice, Inbred C3H; Osteogenesis; Phenotype; Polymorphism, Single Nucleotide; Pregnancy; Proteins
PubMed: 30790652
DOI: 10.1016/j.gene.2019.02.034