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F1000Research 2019Lenz-Majewski syndrome (LMS) is characterized by osteosclerosis and hyperostosis of skull, vertebrae and tubular bones as well as craniofacial, dental, cutaneous, and...
Lenz-Majewski syndrome (LMS) is characterized by osteosclerosis and hyperostosis of skull, vertebrae and tubular bones as well as craniofacial, dental, cutaneous, and digit abnormalities. We previously found that LMS is caused by dominant missense mutations in the gene, which encodes phosphatidylserine synthase 1 (PSS1), an enzyme that catalyses the conversion of phosphatidylcholine to phosphatidylserine. The mutations causing LMS result in a gain-of-function, leading to increased enzyme activity and blocking end-product inhibition of PSS1. Here, we have used transpose-mediated transgenesis to attempt to stably express wild-type and mutant forms of human ubiquitously or specifically in chondrocytes, osteoblasts or osteoclasts in zebrafish. We report multiple genomic integration sites for each of 8 different transgenes. While we confirmed that the ubiquitously driven transgene constructs were functional in terms of driving gene expression following transient transfection in HeLa cells, and that all lines exhibited expression of a heart-specific cistron within the transgene, we failed to detect gene expression at either the RNA or protein levels in zebrafish. All wild-type and mutant transgenic lines of zebrafish exhibited mild scoliosis with variable incomplete penetrance which was never observed in non-transgenic animals. Collectively the data suggest that the transgenes are silenced, that animals with integrations that escape silencing are not viable, or that other technical factors prevent transgene expression. In conclusion, the incomplete penetrance of the phenotype and the lack of a matched transgenic control model precludes further meaningful investigations of these transgenic lines.
Topics: Animals; Animals, Genetically Modified; CDP-Diacylglycerol-Inositol 3-Phosphatidyltransferase; Cell Lineage; HeLa Cells; Humans; Nitrogenous Group Transferases; Short Rib-Polydactyly Syndrome; Transgenes; Zebrafish
PubMed: 31231513
DOI: 10.12688/f1000research.17314.1 -
BMJ Case Reports May 2019Microcephalic osteodysplastic primordial dwarfism syndrome II (MOPDII) is microcephalic primordial dwarfism and is a very rare form of disproportionate short stature....
Microcephalic osteodysplastic primordial dwarfism syndrome II (MOPDII) is microcephalic primordial dwarfism and is a very rare form of disproportionate short stature. This disorder shares common features with other forms of microcephalic primordial dwarfism, including severe prenatal and postnatal growth retardation with marked microcephaly. However, it includes characteristic skeletal dysplasia, abnormal dentition and increased risk for cerebrovascular diseases. Recent reports added more features, including café-au-lait lesions, cutis marmorata, astigmatism, Moyamoya disease, insulin resistance, obesity, abnormal skin pigmentation and acanthosis nigricans around the neck. Clearly, the more MOPDII reports that are produced, the more information will be added to the spectrum of MOPDII features that can improve our understanding of this disorder. In this paper, we reported a new case of MOPDII with more severe clinical features, earlier onset of common features, in addition to a homozygous novel variant in the gene.
Topics: Antigens; Consanguinity; Dwarfism; Feeding and Eating Disorders; Fetal Growth Retardation; Homozygote; Humans; Infant; Male; Microcephaly; Nervous System Diseases; Osteochondrodysplasias; Parenteral Nutrition; Rare Diseases
PubMed: 31151966
DOI: 10.1136/bcr-2018-224197 -
Taiwanese Journal of Obstetrics &... Aug 2018
Corrigendum to "Identification of a c.544C>T mutation in WDR34 as a deleterious recessive allele of short rib-polydactyly syndrome" [Taiwanese Journal of Obstetrics & Gynecology 56 (2017) 857-862].
PubMed: 30122595
DOI: 10.1016/j.tjog.2018.06.031 -
American Journal of Human Genetics Jul 2018Next-generation sequencing has been invaluable in the elucidation of the genetic etiology of many subtypes of intellectual disability in recent years. Here, using exome...
Next-generation sequencing has been invaluable in the elucidation of the genetic etiology of many subtypes of intellectual disability in recent years. Here, using exome sequencing and whole-genome sequencing, we identified three de novo truncating mutations in WAS protein family member 1 (WASF1) in five unrelated individuals with moderate to profound intellectual disability with autistic features and seizures. WASF1, also known as WAVE1, is part of the WAVE complex and acts as a mediator between Rac-GTPase and actin to induce actin polymerization. The three mutations connected by Matchmaker Exchange were c.1516C>T (p.Arg506Ter), which occurs in three unrelated individuals, c.1558C>T (p.Gln520Ter), and c.1482delinsGCCAGG (p.Ile494MetfsTer23). All three variants are predicted to partially or fully disrupt the C-terminal actin-binding WCA domain. Functional studies using fibroblast cells from two affected individuals with the c.1516C>T mutation showed a truncated WASF1 and a defect in actin remodeling. This study provides evidence that de novo heterozygous mutations in WASF1 cause a rare form of intellectual disability.
Topics: Adult; Female; Heterozygote; Humans; Intellectual Disability; Male; Mutation; Seizures; Exome Sequencing; Wiskott-Aldrich Syndrome Protein Family; Young Adult
PubMed: 29961568
DOI: 10.1016/j.ajhg.2018.06.001 -
Taiwanese Journal of Obstetrics &... Feb 2018We present the perinatal imaging findings and molecular genetic analysis in a fetus with short-rib polydactyly syndrome (SRPS) type III or short-rib thoracic dysplasia 3...
Prenatal diagnosis of short-rib polydactyly syndrome type III or short-rib thoracic dysplasia 3 with or without polydactyly (SRTD3) associated with compound heterozygous mutations in DYNC2H1 in a fetus.
OBJECTIVE
We present the perinatal imaging findings and molecular genetic analysis in a fetus with short-rib polydactyly syndrome (SRPS) type III or short-rib thoracic dysplasia 3 with or without polydactyly (SRTD3).
CASE REPORT
A 29-year-old, primigravid woman was referred for genetic counseling at 15 weeks of gestation because of abnormal ultrasound findings of short limbs, a narrow chest and bilateral polydactyly of the hands and feet, consistent with a diagnosis of SRPS type III. Chorionic villus sampling was performed, and targeted next-generation sequencing (NGS) was applied to analyze a panel of 25 genes including CEP120, DYNC2H1, DYNC2LI1, EVC, EVC2, FGFR2, FGFR3, HOXD10, IFT122, IFT140, IFT172, IFT52, IFT80, KIAA0586, NEK1, PAPSS2, SLC26A2, SOX9, TCTEX1D2, TCTN3, TTC21B, WDR19, WDR34, WDR35 and WDR60. The NGS analysis identified novel mutations in the DYNC2H1 gene. The fetus was compound heterozygous for a missense mutation c.8077G > T (p.Asp2693Tyr) of paternal origin in DYNC2H1 and a frameshift mutation c.11741_11742delTT (p.Phe3914X) of maternal origin in DYNC2H1. The fetus had a karyotype of 46,XY, and postnatally manifested characteristic SRPS type III phenotype.
CONCLUSION
Targeted NGS is useful in genetic diagnosis of fetal skeletal dysplasia and SRPS, and the information acquired is helpful in genetic counseling.
Topics: Adult; Chorionic Villi Sampling; Cytoplasmic Dyneins; Female; Fetus; High-Throughput Nucleotide Sequencing; Humans; Mutation; Polydactyly; Pregnancy; Short Rib-Polydactyly Syndrome; Ultrasonography, Prenatal
PubMed: 29458881
DOI: 10.1016/j.tjog.2017.12.021 -
American Journal of Medical Genetics.... Mar 2018The cutis laxa syndromes are multisystem disorders that share loose redundant inelastic and wrinkled skin as a common hallmark clinical feature. The underlying molecular... (Review)
Review
The cutis laxa syndromes are multisystem disorders that share loose redundant inelastic and wrinkled skin as a common hallmark clinical feature. The underlying molecular defects are heterogeneous and 13 different genes have been involved until now, all of them being implicated in elastic fiber assembly. We provide here molecular and clinical characterization of three unrelated patients with a very rare phenotype associating cutis laxa, facial dysmorphism, severe growth retardation, hyperostotic skeletal dysplasia, and intellectual disability. This disorder called Lenz-Majewski syndrome (LMS) is associated with gain of function mutations in PTDSS1, encoding an enzyme involved in phospholipid biosynthesis. This report illustrates that LMS is an unequivocal cutis laxa syndrome and expands the clinical and molecular spectrum of this group of disorders. In the neonatal period, brachydactyly and facial dysmorphism are two early distinctive signs, later followed by intellectual disability and hyperostotic skeletal dysplasia with severe dwarfism allowing differentiation of this condition from other cutis laxa phenotypes. Further studies are needed to understand the link between PTDSS1 and extra cellular matrix assembly.
Topics: Adult; Alleles; Child; Child, Preschool; Cutis Laxa; Exons; Facies; Female; Genetic Association Studies; Genotype; Humans; Hyperostosis; Male; Mutation; Nitrogenous Group Transferases; Phenotype; Radiography
PubMed: 29341480
DOI: 10.1002/ajmg.a.38604 -
Taiwanese Journal of Obstetrics &... Dec 2017Single-nucleotide polymorphism (SNP) microarrays and whole-exome sequencing (WES) are tools to precisely diagnose rare autosomal recessive (AR) diseases. In this study,...
OBJECTIVE
Single-nucleotide polymorphism (SNP) microarrays and whole-exome sequencing (WES) are tools to precisely diagnose rare autosomal recessive (AR) diseases. In this study, SNP chip and WES were used to identify a mutated location in WDR34 in a baby born to consanguineous parents.
CASE REPORT
The baby, born at 36 gestational weeks had a small thoracic cage, symmetric short proximal bones, and polydactyly. Radiography showed short ribs with reduced lung volume and pulmonary opacities, compatible with asphyxiating thoracic dystrophy or short rib-polydactyly syndrome (SRPS). At 4 months of age, she died of pulmonary hypoplasia and sepsis. SNP microarray and evaluation tool confirmed WDR34 as the candidate gene. WES detected an AR mutation at c.554C > T [p.Arg182Trp] in WDR34.
CONCLUSION
This study was the first to identify c.544C > T [p.Arg182Trp] mutation in WDR34 in a patient with SRPS. According to the database, the homozygous mutation of c.544C > T in WDR34 was deleterious and the prevalence of heterozygous mutation was relatively higher in Asian population. More studies of this mutation in patients with SRPS are required.
Topics: Alleles; Carrier Proteins; Consanguinity; Fatal Outcome; Female; Humans; Infant; Infant, Newborn; Mutation; Short Rib-Polydactyly Syndrome
PubMed: 29241935
DOI: 10.1016/j.tjog.2017.10.033 -
Human Mutation Jan 2018Defects in the biosynthesis and/or function of primary cilia cause a spectrum of disorders collectively referred to as ciliopathies. A subset of these disorders is...
Defects in the biosynthesis and/or function of primary cilia cause a spectrum of disorders collectively referred to as ciliopathies. A subset of these disorders is distinguished by profound abnormalities of the skeleton that include a long narrow chest with markedly short ribs, extremely short limbs, and polydactyly. These include the perinatal lethal short-rib polydactyly syndromes (SRPS) and the less severe asphyxiating thoracic dystrophy (ATD), Ellis-van Creveld (EVC) syndrome, and cranioectodermal dysplasia (CED) phenotypes. To identify new genes and define the spectrum of mutations in the skeletal ciliopathies, we analyzed 152 unrelated families with SRPS, ATD, and EVC. Causal variants were discovered in 14 genes in 120 families, including one newly associated gene and two genes previously associated with other ciliopathies. These three genes encode components of three different ciliary complexes; FUZ, which encodes a planar cell polarity complex molecule; TRAF3IP1, which encodes an anterograde ciliary transport protein; and LBR, which encodes a nuclear membrane protein with sterol reductase activity. The results established the molecular basis of SRPS type IV, in which mutations were identified in four different ciliary genes. The data provide systematic insight regarding the genotypes associated with a large cohort of these genetically heterogeneous phenotypes and identified new ciliary components required for normal skeletal development.
Topics: Ciliopathies; Cytoplasmic Dyneins; Genetic Association Studies; Genetic Markers; Genetic Variation; Genotype; Humans; Intercellular Signaling Peptides and Proteins; Mutation; Phenotype; Proteins; Radiography; Skeleton; Exome Sequencing
PubMed: 29068549
DOI: 10.1002/humu.23362 -
Current Biology : CB May 2017Cytoplasmic dynein-2 powers retrograde intraflagellar transport that is essential for cilium formation and maintenance. Inactivation of dynein-2 by mutations in DYNC2H1...
Cytoplasmic dynein-2 powers retrograde intraflagellar transport that is essential for cilium formation and maintenance. Inactivation of dynein-2 by mutations in DYNC2H1 causes skeletal dysplasias, and it remains unclear how the dynein-2 heavy chain moves in cilia. Here, using the genome-editing technique to produce fluorescent dynein-2 heavy chain in Caenorhabditis elegans, we show by high-resolution live microscopy that dynein-2 moves in a surprising way along distinct ciliary domains. Dynein-2 shows triphasic movement in the retrograde direction: dynein-2 accelerates in the ciliary distal region and then moves at maximum velocity and finally decelerates adjacent to the base, which may represent a physical obstacle due to transition zone barriers. By knocking the conserved ciliopathy-related mutations into the C. elegans dynein-2 heavy chain, we find that these mutations reduce its transport speed and frequency. Disruption of the dynein-2 tail domain, light intermediate chain, or intraflagellar transport (IFT)-B complex abolishes dynein-2's ciliary localization, revealing their important roles in ciliary entry of dynein-2. Furthermore, our affinity purification and genetic analyses show that IFT-A subunits IFT-139 and IFT-43 function redundantly to promote dynein-2 motility. These results reveal the molecular regulation of dynein-2 movement in sensory cilia.
Topics: Amino Acid Sequence; Animals; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Cilia; Dyneins; Flagella; Genomics; Mutation; Protein Subunits; Protein Transport; Sensory Receptor Cells; Sequence Homology
PubMed: 28479320
DOI: 10.1016/j.cub.2017.04.015 -
Cilia 2017Skeletal ciliopathies comprise a spectrum of ciliary malfunction disorders that have a profound effect on the skeleton. Most common among these disorders is short rib...
BACKGROUND
Skeletal ciliopathies comprise a spectrum of ciliary malfunction disorders that have a profound effect on the skeleton. Most common among these disorders is short rib polydactyly syndrome (SRPS), a recessively inherited perinatal lethal condition characterized by a long narrow chest, markedly shortened long bones, polydactyly and, often, multi-organ system involvement. SRPS shows extensive locus heterogeneity with mutations in genes encoding proteins that participate in cilia formation and/or function.
RESULTS
Herein we describe mutations in , a satellite member of the retrograde IFT-A complex, that produce a form of SRPS with unusual bending of the ribs and appendicular bones. These newly described mutations disrupted cilia formation, produced abnormalities in cartilage growth plate architecture thus contributing to altered endochondral ossification. We further show that the SRPS phenotype is similar to SRPS resulting from mutations in the gene encoding IFT121 (WDR35), a direct interactor with IFT43.
CONCLUSIONS
This study defines a new -associated phenotype, identifying an additional locus for SRPS. The data demonstrate that IFT43 is essential for ciliogenesis and that the mutations disrupted the orderly proliferation and differentiation of growth plate chondrocytes, resulting in a severe effect on endochondral ossification and mineralization. Phenotypic similarities with SRPS cases resulting from mutations in the gene encoding the IFT43 direct interacting protein IFT121 suggests that similar mechanisms may be disrupted by defects in these two IFT-A satellite interactors.
PubMed: 28400947
DOI: 10.1186/s13630-017-0051-y