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American Journal of Human Genetics Jan 2011Defects of ciliogenesis have been implicated in a wide range of human phenotypes and play a crucial role in signal transduction and cell-cycle coordination. We used...
Defects of ciliogenesis have been implicated in a wide range of human phenotypes and play a crucial role in signal transduction and cell-cycle coordination. We used homozygosity mapping in two families with autosomal-recessive short-rib polydactyly syndrome Majewski type to identify mutations in NEK1 as an underlying cause of this lethal osteochondrodysplasia. NEK1 encodes a serine/threonine kinase with proposed function in DNA double-strand repair, neuronal development, and coordination of cell-cycle-associated ciliogenesis. We found that absence of functional full-length NEK1 severely reduces cilia number and alters ciliar morphology in vivo. We further substantiate a proposed digenic diallelic inheritance of ciliopathies by the identification of heterozygous mutations in NEK1 and DYNC2H1 in an additional family. Notably, these findings not only increase the broad spectrum of ciliar disorders, but suggest a correlation between the degree of defective microtubule or centriole elongation and organization and the severity of the resulting phenotype.
Topics: Cell Cycle Proteins; Chromosome Mapping; Cilia; Cytoplasmic Dyneins; DNA Repair; Female; Genes, Recessive; Heterozygote; Humans; Male; Mutation; NIMA-Related Kinase 1; Phenotype; Protein Serine-Threonine Kinases; Radiography; Sequence Analysis, DNA; Severity of Illness Index; Short Rib-Polydactyly Syndrome
PubMed: 21211617
DOI: 10.1016/j.ajhg.2010.12.004 -
Japanese Journal of Radiology Mar 2020Ciliopathy encompasses a diverse group of autosomal recessive genetic disorders caused by mutations in genes coding for components of the primary cilia. Skeletal... (Review)
Review
Ciliopathy encompasses a diverse group of autosomal recessive genetic disorders caused by mutations in genes coding for components of the primary cilia. Skeletal ciliopathy forms a subset of ciliopathies characterized by distinctive skeletal changes. Common skeletal ciliopathies include Jeune asphyxiating thoracic dysplasia, Ellis-van Creveld syndrome, Sensenbrenner syndrome, and short-rib polydactyly syndromes. These disorders share common clinical and radiological features. The clinical hallmarks comprise thoracic hypoplasia with respiratory failure, body disproportion with a normal trunk length and short limbs, and severely short digits occasionally accompanied by polydactyly. Reflecting the clinical features, the radiological hallmarks consist of a narrow thorax caused by extremely short ribs, normal or only mildly affected spine, shortening of the tubular bones, and severe brachydactyly with or without polydactyly. Other radiological clues include trident ilia/pelvis and cone-shaped epiphysis. Skeletal ciliopathies are commonly associated with extraskeletal anomalies, such as progressive renal degeneration, liver disease, retinopathy, cardiac anomalies, and cerebellar abnormalities. In this article, we discuss the radiological pattern recognition approach to skeletal ciliopathies. We also describe the clinical and genetic features of skeletal ciliopathies that the radiologists should know for them to play an appropriate role in multidisciplinary care and scientific advancement of these complicated disorders.
Topics: Bone and Bones; Ciliopathies; Craniosynostoses; Dwarfism; Ectodermal Dysplasia; Ellis-Van Creveld Syndrome; Female; Humans; Image Interpretation, Computer-Assisted; Male; Osteochondrodysplasias; Radiography
PubMed: 31965514
DOI: 10.1007/s11604-020-00920-w -
European Journal of Pediatrics Feb 1991We describe the seventh patient with the Floating-Harbor syndrome. Similar to previous cases in the literature this girl presented with proportionate intrauterine and...
We describe the seventh patient with the Floating-Harbor syndrome. Similar to previous cases in the literature this girl presented with proportionate intrauterine and postnatal growth retardation, normocephaly, triangular face with bulbous nose, long eyelashes, short upper lip, small vermilion border of upper lip, dorsally rotated ears, deep nuchal hair line, hirsutism, and clinodactyly of little fingers. She exhibited mental retardation and retarded speech development. Clinical symptoms and differential diagnosis of this rare syndrome are briefly discussed.
Topics: Abnormalities, Multiple; Child; Diagnosis, Differential; Eye Abnormalities; Female; Fetal Growth Retardation; Fingers; Growth Disorders; Hirsutism; Humans; Intellectual Disability; Mouth Abnormalities; Nose; Syndrome
PubMed: 2029915
DOI: 10.1007/BF01955523 -
Cells Jul 2021Although ubiquitously present, the relevance of cilia for vertebrate development and health has long been underrated. However, the aberration or dysfunction of ciliary... (Review)
Review
Although ubiquitously present, the relevance of cilia for vertebrate development and health has long been underrated. However, the aberration or dysfunction of ciliary structures or components results in a large heterogeneous group of disorders in mammals, termed ciliopathies. The majority of human ciliopathy cases are caused by malfunction of the ciliary dynein motor activity, powering retrograde intraflagellar transport (enabled by the cytoplasmic dynein-2 complex) or axonemal movement (axonemal dynein complexes). Despite a partially shared evolutionary developmental path and shared ciliary localization, the cytoplasmic dynein-2 and axonemal dynein functions are markedly different: while cytoplasmic dynein-2 complex dysfunction results in an ultra-rare syndromal skeleto-renal phenotype with a high lethality, axonemal dynein dysfunction is associated with a motile cilia dysfunction disorder, primary ciliary dyskinesia (PCD) or Kartagener syndrome, causing recurrent airway infection, degenerative lung disease, laterality defects, and infertility. In this review, we provide an overview of ciliary dynein complex compositions, their functions, clinical disease hallmarks of ciliary dynein disorders, presumed underlying pathomechanisms, and novel developments in the field.
Topics: Animals; Axonemal Dyneins; Cilia; Ciliopathies; Cytoplasmic Dyneins; Humans; Kartagener Syndrome; Polymorphism, Genetic; Short Rib-Polydactyly Syndrome
PubMed: 34440654
DOI: 10.3390/cells10081885 -
Journal of Inherited Metabolic Disease Jan 2015Since the proposal to define a separate subgroup of inborn errors of metabolism involved in the biosynthesis and remodelling of phospholipids, sphingolipids and long... (Review)
Review
Since the proposal to define a separate subgroup of inborn errors of metabolism involved in the biosynthesis and remodelling of phospholipids, sphingolipids and long chain fatty acids in 2013, this group is rapidly expanding. This review focuses on the disorders involved in the biosynthesis of phospholipids. Phospholipids are involved in uncountable cellular processes, e.g. as structural components of membranes, by taking part in vesicle and mitochondrial fusion and fission or signal transduction. Here we provide an overview on both pathophysiology and the extremely heterogeneous clinical presentations of the disorders reported so far (Sengers syndrome (due to mutations in AGK), MEGDEL syndrome (or SERAC defect, SERAC1), Barth syndrome (or TAZ defect, TAZ), congenital muscular dystrophy due to CHKB deficiency (CHKB). Boucher-Neuhäuser/Gordon Holmes syndrome (PNPLA6), PHARC syndrome (ABHD12), hereditary spastic paraplegia type 28, 54 and 56 (HSP28, DDHD1; HSP54, DDHD2; HSP56, CYP2U1), Lenz Majewski syndrome (PTDSS1), spondylometaphyseal dysplasia with cone-rod dystrophy (PCYT1A), atypical haemolytic-uremic syndrome due to DGKE deficiency (DGKE).
Topics: Anophthalmos; Barth Syndrome; Cardiomyopathies; Cataract; Cerebellar Ataxia; Family Health; Gonadotropin-Releasing Hormone; Hemolytic-Uremic Syndrome; Humans; Hypogonadism; Metabolism, Inborn Errors; Microphthalmos; Muscular Dystrophies; Mutation; Osteochondrodysplasias; Phospholipids; Spastic Paraplegia, Hereditary
PubMed: 25178427
DOI: 10.1007/s10545-014-9759-7 -
Nature Genetics Jan 2014Lenz-Majewski syndrome (LMS) is a syndrome of intellectual disability and multiple congenital anomalies that features generalized craniotubular hyperostosis. By using...
Lenz-Majewski syndrome (LMS) is a syndrome of intellectual disability and multiple congenital anomalies that features generalized craniotubular hyperostosis. By using whole-exome sequencing and selecting variants consistent with the predicted dominant de novo etiology of LMS, we identified causative heterozygous missense mutations in PTDSS1, which encodes phosphatidylserine synthase 1 (PSS1). PSS1 is one of two enzymes involved in the production of phosphatidylserine. Phosphatidylserine synthesis was increased in intact fibroblasts from affected individuals, and end-product inhibition of PSS1 by phosphatidylserine was markedly reduced. Therefore, these mutations cause a gain-of-function effect associated with regulatory dysfunction of PSS1. We have identified LMS as the first human disease, to our knowledge, caused by disrupted phosphatidylserine metabolism. Our results point to an unexplored link between phosphatidylserine synthesis and bone metabolism.
Topics: Abnormalities, Multiple; Adolescent; Animals; Cells, Cultured; Child; Dwarfism; Embryo, Nonmammalian; Female; Fibroblasts; Humans; Hyperostosis; Male; Molecular Sequence Data; Mutation; Nitrogenous Group Transferases; Phosphatidylserines; Syndrome; Zebrafish
PubMed: 24241535
DOI: 10.1038/ng.2829 -
American Journal of Medical Genetics Oct 1996Patients with the autosomal dominant ble-pharo-cheilo-dontic (BCD) syndrome have ectropion of lower eyelids, distichiasis of upper eyelids, euryblepharon, bilaterally...
Patients with the autosomal dominant ble-pharo-cheilo-dontic (BCD) syndrome have ectropion of lower eyelids, distichiasis of upper eyelids, euryblepharon, bilaterally cleft lip/palate, oligodontia, and conical crown form. Initially known under the eponym "Elschnig syndrome" (1912), BCD syndrome has been described in binary, ternary, and quaternary combination. There is overlap with the syndrome reported by Martínez et al. [1987], postaxial acrofacial dysostosis (Miller syndrome, Genée-Wiedemann syndrome), and a syndrome reported briefly by Warburg.
Topics: Child; Child, Preschool; Cleft Lip; Cleft Palate; Ectropion; Eyelids; Female; Humans; Hypertelorism; Infant; Male; Syndrome; Tooth Abnormalities
PubMed: 8911600
DOI: 10.1002/(SICI)1096-8628(19961016)65:2<109::AID-AJMG5>3.0.CO;2-N -
European Journal of Pediatrics Sep 2012Cilia are antenna-like organelles found on the surface of most cells. They transduce molecular signals and facilitate interactions between cells and their environment.... (Review)
Review
Cilia are antenna-like organelles found on the surface of most cells. They transduce molecular signals and facilitate interactions between cells and their environment. Ciliary dysfunction has been shown to underlie a broad range of overlapping, clinically and genetically heterogeneous phenotypes, collectively termed ciliopathies. Literally, all organs can be affected. Frequent cilia-related manifestations are (poly)cystic kidney disease, retinal degeneration, situs inversus, cardiac defects, polydactyly, other skeletal abnormalities, and defects of the central and peripheral nervous system, occurring either isolated or as part of syndromes. Characterization of ciliopathies and the decisive role of primary cilia in signal transduction and cell division provides novel insights into tumorigenesis, mental retardation, and other common causes of morbidity and mortality, including diabetes mellitus and obesity. New technologies ("Next generation sequencing/NGS") have considerably improved genetic research and diagnostics by allowing simultaneous investigation of all disease genes at reduced costs and lower turn-around times. This is undoubtedly a result of the dynamic development in the field of human genetics and deserves increased attention in genetic counselling and the management of affected families.
Topics: Bardet-Biedl Syndrome; Ciliary Motility Disorders; Genetic Testing; Humans; Kidney Diseases, Cystic; Short Rib-Polydactyly Syndrome
PubMed: 21898032
DOI: 10.1007/s00431-011-1553-z -
Molecular Vision 2021Cytoplasmic dyneins (dynein-1 and dynein-2) transport cargo toward the minus end of microtubules and thus, are termed the "retrograde" cellular motor. Dynein-1 cargo may... (Review)
Review
Cytoplasmic dyneins (dynein-1 and dynein-2) transport cargo toward the minus end of microtubules and thus, are termed the "retrograde" cellular motor. Dynein-1 cargo may include nuclei, mitochondria, membrane vesicles, lysosomes, phagosomes, and other organelles. For example, dynein-1 works in the cell body of eukaryotes to move cargo toward the microtubule minus end and positions the Golgi complex. Dynein-1 also participates in the movement of chromosomes and the positioning of mitotic spindles during cell division. In contrast, dynein-2 is present almost exclusively within cilia where it participates in retrograde intraflagellar transport (IFT) along the axoneme to return kinesin-2 subunits, BBSome, and IFT particles to the cell body. Cytoplasmic dyneins are hefty 1.5 MDa complexes comprised of dimers of heavy, intermediate, light intermediate, and light chains. Missense mutations of human are associated with malformations of cortical development (MCD) or spinal muscular atrophy with lower extremity predominance (SMA-LED). Missense mutations in are causative of short-rib polydactyly syndrome type III and nonsyndromic retinitis pigmentosa. We review mutations of the two dynein heavy chains and their effect on postnatal retina development and discuss consequences of deletion of in the mouse retina.
Topics: Animals; Cytoplasmic Dyneins; Gene Expression; Humans; Mice; Mutation; Photoreceptor Cells, Vertebrate; Retinal Diseases
PubMed: 34526758
DOI: No ID Found -
European Journal of Human Genetics :... May 2015So far very few patients with sequence variants in the closely related tectonic genes TCTN1-3 have been described. By multi-gene panel next-generation sequencing (NGS)... (Review)
Review
So far very few patients with sequence variants in the closely related tectonic genes TCTN1-3 have been described. By multi-gene panel next-generation sequencing (NGS) in patients with Joubert syndrome, we identified two more patients and summarize what is currently known about the phenotypes associated with sequence variants in these genes. In a boy aged 12 years with intellectual disability and the classical molar tooth sign on MRI, a homozygous splice-site sequence variant in TCTN3 leading to in-frame skipping of exon 7 was detected. A previously described non-truncating sequence variant in TCTN3 was also associated with Joubert syndrome, whereas four truncating sequence variants were detected in patients with Meckel-Gruber or Mohr-Majewski syndrome. The second patient, a boy aged 7 years with severe psychomotor retardation, was found to carry a homozygous canonic splice-site sequence variant in TCTN2. So far, only three sequence variants associated with Joubert syndrome and two with Meckel-Gruber syndrome have been described in this gene. Reviewing the clinical data on patients with sequence variants in the tectonic genes TCTN1-3 reveals that all of them have a neurological phenotype with vermis hypoplasia or occipital encephalocele associated with severe intellectual disability in the surviving patients. In contrast, other features frequently seen in patients with ciliopathies such as nephronophthisis, liver fibrosis, retinal dystrophy or coloboma have not been reported. Our patients emphasize the usefulness and efficacy of a comprehensive NGS panel approach. A concise genetic diagnosis may help to prevent unnecessary investigations and improve the clinical management of these patients.
Topics: Abnormalities, Multiple; Adaptor Proteins, Signal Transducing; Apoptosis Regulatory Proteins; Cerebellar Vermis; Cerebellum; DNA Mutational Analysis; Eye Abnormalities; Female; Genotype; High-Throughput Nucleotide Sequencing; Humans; Infant; Intracellular Signaling Peptides and Proteins; Kidney Diseases, Cystic; Magnetic Resonance Imaging; Male; Membrane Proteins; Mutation; Phenotype; Radiography; Retina; Tooth
PubMed: 25118024
DOI: 10.1038/ejhg.2014.160