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European Journal of Medical Genetics Apr 2024Lenz-Majewski hyperostotic dwarfism (LMHD) is a rare condition characterized by intellectual disability, sclerosing bone dysplasia, dysmorphic facial features,...
Lenz-Majewski hyperostotic dwarfism (LMHD) is a rare condition characterized by intellectual disability, sclerosing bone dysplasia, dysmorphic facial features, brachydactyly, symphalangism and cutis laxa. Nineteen cases have been reported in the literature so far, eleven of them with PTDSS1 mutations. Although studies have had clinically similar findings, in some cases the authors have reported even rarer features such as hydrocephalus, facial paralysis, and cleft palate. We, hereby, report the case of the first patient with Lenz-Majewski syndrome (LMS) with molecular confirmation from Turkey. Although our patient had characteristic features described in the literature, she also had immunodeficiency, which has not been reported before. Although there is no established phenotype-genotype correlation, molecular mechanisms can be explained with the reporting of more patients.
Topics: Female; Humans; Intellectual Disability; Short Rib-Polydactyly Syndrome; Bone Diseases, Developmental; Otitis Media; Abnormalities, Multiple
PubMed: 38262577
DOI: 10.1016/j.ejmg.2024.104910 -
BMC Medical Genomics Dec 2023Short-rib polydactyly syndrome (SRPS) refers to a group of lethal skeletal dysplasias that can be difficult to differentiate between subtypes or from other non-lethal...
BACKGROUND
Short-rib polydactyly syndrome (SRPS) refers to a group of lethal skeletal dysplasias that can be difficult to differentiate between subtypes or from other non-lethal skeletal dysplasias such as Ellis-van Creveld syndrome and Jeune syndrome in a prenatal setting. We report the ultrasound and genetic findings of four unrelated fetuses with skeletal dysplasias.
METHODS
Systemic prenatal ultrasound examination was performed in the second or third trimester. Genetic tests including GTG-banding, single nucleotide polymorphism (SNP) array and exome sequencing were performed with amniocytes or aborted fetal tissues.
RESULTS
The major and common ultrasound anomalies for the four unrelated fetuses included short long bones of the limbs and narrow thorax. No chromosomal abnormalities and pathogenic copy number variations were detected. Exome sequencing revealed three novel variants in the DYNC2H1 gene, namely NM_001080463.2:c.6809G > A p.(Arg2270Gln), NM_001080463.2:3133C > T p.(Gln1045Ter), and NM_001080463.2:c.337C > T p.(Arg113Trp); one novel variant in the IFT172 gene, NM_015662.3:4540-5 T > A; and one novel variant in the WDR19 gene, NM_025132.4:c.2596G > C p.(Gly866Arg). The genotypes of DYNC2H1, IFT172 and WDR19 and the phenotypes of the fetuses give hints for the diagnosis of short-rib thoracic dysplasia (SRTD) with or without polydactyly 3, 10, and 5, respectively.
CONCLUSION
Our findings expand the mutation spectrum of DYNC2H1, IFT172 and WDR19 associated with skeletal ciliopathies, and provide useful information for prenatal diagnosis and genetic counseling on rare skeletal disorders.
Topics: Pregnancy; Female; Humans; DNA Copy Number Variations; Ellis-Van Creveld Syndrome; Prenatal Diagnosis; Osteochondrodysplasias; Polydactyly; Ciliopathies; Cytoskeletal Proteins; Adaptor Proteins, Signal Transducing
PubMed: 38062428
DOI: 10.1186/s12920-023-01753-y -
Nucleic Acids Research Dec 2023Molnupiravir (EIDD-2801) is an antiviral that received approval for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infection. Treatment of...
Molnupiravir (EIDD-2801) is an antiviral that received approval for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infection. Treatment of bacteria or cell lines with the active form of molnupiravir, β-d-N4-hydroxycytidine (NHC, or EIDD-1931), induces mutations in DNA. Yet these results contrast in vivo genotoxicity studies conducted during registration of the drug. Using a CRISPR screen, we found that inactivating the pyrimidine salvage pathway component uridine-cytidine kinase 2 (Uck2) renders cells more tolerant of NHC. Short-term exposure to NHC increased the mutation rate in a mouse myeloid cell line, with most mutations being T:A to C:G transitions. Inactivating Uck2 impaired the mutagenic activity of NHC, whereas over-expression of Uck2 enhanced mutagenesis. UCK2 is upregulated in many cancers and cell lines. Our results suggest differences in ribonucleoside metabolism contribute to the variable mutagenicity of NHC observed in cancer cell lines and primary tissues.
Topics: Animals; Mice; Antiviral Agents; Cytidine; Mutagenesis; Mutagens; RNA, Viral; Uridine Kinase
PubMed: 37953355
DOI: 10.1093/nar/gkad1002 -
Journal of Clinical Medicine Oct 2023Electrolyte disturbances related to sodium and potassium affect patients with mental disorders undergoing electroconvulsive therapy (ECT). The objective of this study... (Review)
Review
INTRODUCTION
Electrolyte disturbances related to sodium and potassium affect patients with mental disorders undergoing electroconvulsive therapy (ECT). The objective of this study was to systematically summarize the data regarding ECT and electrolyte disturbances related to sodium and potassium.
MATERIALS AND METHODS
A systematic literature review in accordance with PRISMA guidelines was conducted. Clinical studies of patients receiving ECT with electrolyte disturbances reported before or after treatment were included.
RESULTS
We identified nine case reports and two retrospective studies describing electrolyte abnormalities occurring before or after ECT. ECT was effective and safe in patients with hyponatremia and hypernatremia, including the elderly patient population. This treatment was also effective in treating psychiatric symptoms that may persist after ionic equalization. Electrolyte disturbances after ECT were rare. Reports have suggested that succinylcholine used as a muscle relaxant was the main cause of hyperkalemia after ECT.
CONCLUSIONS
Electrolyte control is a crucial aspect of guiding ECT therapy. In the context of sodium-related disorders, it is critical to control patient hydration as part of therapy. In addition, succinylcholine should not be used in patients with immobilization, such as catatonia or neuroleptic malignant syndrome. It is necessary to conduct further studies to clarify whether electrolyte concentration affects ECT parameters and clinical efficacy. In addition, it is necessary to assess the influence of various anesthetics on these conditions during ECT. The result of this review should be interpreted bearing in mind the small number of studies conducted to date and the low quality of the evidence they provide.
PubMed: 37892815
DOI: 10.3390/jcm12206677 -
Journal of Lipid Research Nov 2023Phosphatidylserine (PS) is an acidic phospholipid that is involved in various cellular events. Heterologous dominant mutations have been identified in the gene encoding...
Phosphatidylserine (PS) is an acidic phospholipid that is involved in various cellular events. Heterologous dominant mutations have been identified in the gene encoding PS synthase 1 (PSS1) in patients with a congenital disease called Lenz-Majewski syndrome (LMS). Patients with LMS show various symptoms, including craniofacial/distal-limb bone dysplasia and progressive hyperostosis. The LMS-causing gain-of-function mutants of PSS1 (PSS1) have been shown to synthesize PS without control, but why the uncontrolled synthesis would lead to LMS is unknown. Here we investigated the effect of PSS1 on osteoclasts (OCs) to elucidate the causative mechanism of LMS. PSS1 did not affect the expression of OC-related genes but inhibited the formation, multinucleation, and activity of OCs. Especially, OCs expressing PSS1 showed abnormal patterns and dynamics of actin podosome clusters, which have roles in OC migration and fusion. PSS1 did not affect the level of PS but changed the acyl chain compositions of PS and phosphatidylethanolamine, and decreased the level of phosphatidylinositol. The introduction of a catalytically inactive mutation into PSS canceled the changes in phospholipids and the phenotypes observed in OCs expressing PSS1. A gain-of-function mutant of PSS2 (PSS2 R97K) also impaired OC formation and caused changes in phospholipid composition similar to the changes caused by PSS1. Our results suggest that uncontrolled PS synthesis by PSS1 causes changes in the quantity or fatty acid composition of certain phospholipid classes, impairing OC formation and function, which might be a cause of osteosclerosis in patients with LMS.
Topics: Humans; Abnormalities, Multiple; Intellectual Disability; Osteoclasts; Phospholipids
PubMed: 37714410
DOI: 10.1016/j.jlr.2023.100443 -
The Journal of Maternal-fetal &... Dec 2023Short-rib thoracic dysplasia 3 with or without polydactyly (OMIM # 613091) represents a clinical spectrum encompassing a heterogeneous group of skeletal dysplasias...
Early prenatal diagnosis of a recurrent case of short-rib thoracic dysplasia 3 due to compound heterozygosity for variations in the DYNC2H1 gene: an "ultrasound first" approach.
Short-rib thoracic dysplasia 3 with or without polydactyly (OMIM # 613091) represents a clinical spectrum encompassing a heterogeneous group of skeletal dysplasias associated with homozygous or compound heterozygous mutations of DYNC2H1. We describe the case of a couple with two consecutive therapeutic abortions due to a diagnosis of short-rib thoracic dysplasia mutations. In the first pregnancy, the diagnosis has been made at 21 weeks. In the second one, an accurate and early ultrasound examination allowed a diagnosis at 12 weeks. DYNC2H1 mutations were confirmed in both cases. In this report, we underline the importance of an ultrasound evaluation at the end of the first trimester of pregnancy in the detection of early signs of skeletal dysplasias. An early prenatal diagnosis of a short-rib skeletal dysplasia, such as for other severe skeletal dysplasias, is critical to offer a couple the chance of a weighted, informed, and less traumatic decision about the continuation of the pregnancy.
Topics: Pregnancy; Female; Humans; Short Rib-Polydactyly Syndrome; Prenatal Diagnosis; Ultrasonography; Osteochondrodysplasias; Ribs; Ultrasonography, Prenatal; Cytoplasmic Dyneins
PubMed: 37100787
DOI: 10.1080/14767058.2023.2205985 -
European Journal of Human Genetics :... Apr 2023Deleterious variants of DYNC2H1 gene are associated with a wide spectrum of skeletal ciliopathies (SC). We used targeted parallel sequencing to analyze 25 molecularly...
Deleterious variants of DYNC2H1 gene are associated with a wide spectrum of skeletal ciliopathies (SC). We used targeted parallel sequencing to analyze 25 molecularly unsolved families with different SCs. Deleterious DYNC2H1 variants were found in six sporadic patients and two monozygotic (MZ) twins. Clinical diagnoses included short rib-polydactyly type 3 in two cases, and asphyxiating thoracic dystrophy (ATD) in one case. Remarkably, clinical diagnosis fitted with EvC, mixed ATD/EvC and short rib-polydactyly/EvC phenotypes in three sporadic patients and the MZ twins. EvC/EvC-like features always occurred in compound heterozygotes sharing a previously unreported splice site change (c.6140-5A>G) or compound heterozygotes for two missense variants. These results expand the DYNC2H1 mutational repertoire and its clinical spectrum, suggesting that EvC may be occasionally caused by DYNC2H1 variants presumably acting as hypomorphic alleles.
Topics: Humans; Ciliopathies; Cytoplasmic Dyneins; Ellis-Van Creveld Syndrome; Mutation; Polydactyly
PubMed: 36599940
DOI: 10.1038/s41431-022-01276-7 -
Cold Spring Harbor Molecular Case... Dec 2022Biallelic pathogenic variants in are the cause of short-rib thoracic dysplasia type III with or without polydactyly (OMIM #613091), a skeletal ciliopathy characterized...
Biallelic pathogenic variants in are the cause of short-rib thoracic dysplasia type III with or without polydactyly (OMIM #613091), a skeletal ciliopathy characterized by thoracic hypoplasia due to short ribs. In this report, we review the case of a patient who was admitted to the Neonatal Intensive Care Unit (NICU) of Indiana University Health (IUH) for respiratory support after experiencing respiratory distress secondary to a small, narrow chest causing restrictive lung disease. Additional phenotypic features include postaxial polydactyly, short proximal long bones, and ambiguous genitalia were noted. Exome sequencing (ES) revealed a maternally inherited likely pathogenic variant c.10322C > T p.(Leu3448Pro) in the gene. However, there was no variant found on the paternal allele. Microarray analysis to detect deletion or duplication in was normal. Therefore, there was insufficient evidence to establish a molecular diagnosis. To further explore the data and perform additional investigations, the patient was subsequently enrolled in the Undiagnosed Rare Disease Clinic (URDC) at Indiana University School of Medicine (IUSM). The investigators at the URDC performed a reanalysis of the ES raw data, which revealed a paternally inherited deep-intronic variant c.10606-14A > G predicted to create a strong cryptic acceptor splice site. Additionally, the RNA sequencing of fibroblasts demonstrated partial intron retention predicted to cause a premature stop codon and nonsense-mediated mRNA decay (NMD). Droplet digital RT-PCR (RT-ddPCR) showed a drastic reduction by 74% of mRNA levels. As a result, the intronic variant was subsequently reclassified as likely pathogenic resulting in a definitive clinical and genetic diagnosis for this patient. Reanalysis of ES and fibroblast mRNA experiments confirmed the pathogenicity of the splicing variants to supplement critical information not revealed in original ES or CMA reports. The NICU and URDC collaboration ended the diagnostic odyssey for this family; furthermore, its importance is emphasized by the possibility of prenatally diagnosing the mother's current pregnancy.
Topics: Female; Humans; Infant, Newborn; Pregnancy; Cytoplasmic Dyneins; Exome Sequencing; Mutation; Polydactyly; Ribs; RNA, Messenger; Short Rib-Polydactyly Syndrome
PubMed: 36442996
DOI: 10.1101/mcs.a006254 -
Journal of Cell Science Mar 2023The primary cilium is a sensory organelle, receiving signals from the external environment and relaying them into the cell. Mutations in proteins required for transport...
The primary cilium is a sensory organelle, receiving signals from the external environment and relaying them into the cell. Mutations in proteins required for transport in the primary cilium result in ciliopathies, a group of genetic disorders that commonly lead to the malformation of organs such as the kidney, liver and eyes and skeletal dysplasias. The motor proteins dynein-2 and kinesin-2 mediate retrograde and anterograde transport, respectively, in the cilium. WDR34 (also known as DYNC2I2), a dynein-2 intermediate chain, is required for the maintenance of cilia function. Here, we investigated WDR34 mutations identified in Jeune syndrome, short-rib polydactyly syndrome and asphyxiating thoracic dysplasia patients. There is a poor correlation between genotype and phenotype in these cases, making diagnosis and treatment highly complex. We set out to define the biological impacts on cilia formation and function of WDR34 mutations by stably expressing the mutant proteins in WDR34-knockout cells. WDR34 mutations led to different spectrums of phenotypes. Quantitative proteomics demonstrated changes in dynein-2 assembly, whereas initiation and extension of the axoneme, localization of intraflagellar transport complex-B proteins, transition zone integrity and Hedgehog signalling were also affected.
Topics: Humans; Dyneins; Carrier Proteins; Hedgehog Proteins; Ellis-Van Creveld Syndrome; Cilia; Mutation
PubMed: 36268591
DOI: 10.1242/jcs.260073 -
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