-
Journal of Medical Genetics Apr 2023Ellis-Van Creveld (EVC) syndrome is one of the entities belonging to the skeletal ciliopathies short rib-polydactyly subgroup. Major signs are ectodermal dysplasia,...
BACKGROUND
Ellis-Van Creveld (EVC) syndrome is one of the entities belonging to the skeletal ciliopathies short rib-polydactyly subgroup. Major signs are ectodermal dysplasia, chondrodysplasia, polydactyly and congenital cardiopathy, with a high degree of variability in phenotypes ranging from lethal to mild clinical presentations. The and genes are the major genes causative of EVC syndrome. However, an increased number of genes involved in the ciliopathy complex have been identified in EVC syndrome, leading to a better understanding of its physiopathology, namely, , , , , and . They all code for proteins located in the primary cilia, playing a key role in signal transduction of the Hedgehog pathways.
METHODS
The aim of this study was the analysis of 50 clinically identified EVC cases from 45 families to further define the phenotype and molecular bases of EVC.
RESULTS
Our detection rate in the cohort of 45 families was of 91.11%, with variants identified in (77.8%), (6.7%), (2.2%), (2.2%) or (2.2%). No distinctive feature was remarkable of a specific genotype-phenotype correlation. Interestingly, we identified a high proportion of heterozygous deletions in of variable sizes (26.92%), mostly inherited from the mother, and probably resulting from recombinations involving Alu sequences.
CONCLUSION
We confirmed that and are the major genes involved in the EVC phenotype and highlighted the high prevalence of previously unreported CNVs (Copy Number Variation).
Topics: Humans; Hedgehog Proteins; Ellis-Van Creveld Syndrome; DNA Copy Number Variations; Phenotype; Polydactyly
PubMed: 35927022
DOI: 10.1136/jmg-2022-108435 -
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 -
American Journal of Medical Genetics.... Oct 2019Lenz-Majewski syndrome (LMS) is an extremely rare type of cutis laxa caused by dominant mutations in PTDSS1 gene. We report an Egyptian patient who presented with cutis...
Lenz-Majewski syndrome (LMS) is an extremely rare type of cutis laxa caused by dominant mutations in PTDSS1 gene. We report an Egyptian patient who presented with cutis laxa, brachydactyly, and progeroid features. LMS syndrome was suspected and a previously reported de novo heterozygous missense mutation (c.284G > T, p.R95L) in PTDSS1 was identified. To the best of our knowledge, nine molecularly proven patients with LMS from different ethnicities have been reported. Our patient is the first report from the Middle East and the tenth molecularly proven patient reported to date. His clinical features were in accordance with LMS syndrome. In addition, his hands X-ray images showed hypoplastic or absent middle and proximal phalanges but sparing the thumbs. This hand patterning was similarly observed before. Further, he had relatively large and convex fingernails. Our report highlights this unique hand patterning and suggests these signs should be considered among the diagnostic criteria of LMS. Further reports of patients with PTDSS1 mutations are necessary to further elucidate the detailed clinical features of LMS syndrome.
Topics: Abnormalities, Multiple; Bone Diseases, Developmental; Egypt; Exons; Humans; Infant; Intellectual Disability; Introns; Male; Nitrogenous Group Transferases; Syndrome
PubMed: 31403251
DOI: 10.1002/ajmg.a.61327 -
Reumatologia 2016The majority of rheumatic diseases belong to the group of autoimmune diseases and are associated with autoantibody production. Their etiology is not fully understood.... (Review)
Review
The majority of rheumatic diseases belong to the group of autoimmune diseases and are associated with autoantibody production. Their etiology is not fully understood. Certain medications and environmental factors may have an influence on the occurrence of rheumatic diseases. Establishing a cause-effect relationship between a certain factor and disease induction is not always simple. It is important to administer the drug continuously or monitor exposure to a given factor in the period preceding the onset of symptoms. The lack of previously diagnosed autoimmune disease, or finally the lack of symptoms within a few weeks/months after discontinuation of the drug/cessation of exposure, is also important. The most frequently mentioned rheumatic diseases caused by drugs and environmental factors include systemic lupus erythematosus, scleroderma, systemic vasculitis, polymyositis, dermatomyositis, and Sjögren's syndrome. The objective of this study is to summarize current knowledge on rheumatic diseases induced by drugs and environmental factors.
PubMed: 27504022
DOI: 10.5114/reum.2016.61212 -
Reumatologia 2016The majority of rheumatic diseases belong to the group of autoimmune diseases and are associated with autoantibody production. Their etiology is not fully understood.... (Review)
Review
The majority of rheumatic diseases belong to the group of autoimmune diseases and are associated with autoantibody production. Their etiology is not fully understood. Certain medications and environmental factors may have an influence on the occurrence of rheumatic diseases. Establishing a cause-effect relationship between a certain factor and disease induction is not always simple. It is important to administer the drug continuously or monitor exposure to a given factor in the period preceding the onset of symptoms. The lack of early diagnosed autoimmune disease, or finally the lack of symptoms within a few weeks/months after discontinuation of the drug/cessation of exposure, is also important. The most frequently mentioned rheumatic diseases caused by drugs and environmental factors include systemic lupus erythematosus (SLE), scleroderma, systemic vasculitis, polymyositis, dermatomyositis, and Sjögren's syndrome. The objective of this study is to summarize current knowledge on rheumatic diseases induced by drugs and environmental factors.
PubMed: 27826170
DOI: 10.5114/reum.2016.62470 -
Clinical Genetics Dec 2023We studied a patient with mitochondrial DNA depletion in skeletal muscle and a multiorgan phenotype, including fatal encephalomyopathy, retinopathy, optic atrophy, and...
We studied a patient with mitochondrial DNA depletion in skeletal muscle and a multiorgan phenotype, including fatal encephalomyopathy, retinopathy, optic atrophy, and sensorineural hearing loss. Instead of pathogenic variants in the mitochondrial maintenance genes, we identified previously unpublished variant in DHX16 gene, a de novo heterozygous c.1360C>T (p. Arg454Trp). Variants in DHX16 encoding for DEAH-box RNA helicase have previously been reported only in five patients with a phenotype called as neuromuscular oculoauditory syndrome including developmental delay, neuromuscular symptoms, and ocular or auditory defects with or without seizures. We performed functional studies on patient-derived fibroblasts and skeletal muscle revealing, that the DHX16 expression was decreased. Clinical features together with functional data suggest, that our patient's disease is associated with a novel pathogenic DHX16 variant, and mtDNA depletion could be a secondary manifestation of the disease.
Topics: Humans; DNA, Mitochondrial; Metabolism, Inborn Errors; Muscle, Skeletal; Optic Atrophy; Retinal Diseases; RNA Helicases; Infant
PubMed: 37574199
DOI: 10.1111/cge.14416 -
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 -
International Journal of Molecular... Sep 2021The Hedgehog (HH) signalling pathway is one of the major pathways controlling cell differentiation and proliferation during human development. This pathway is complex,... (Review)
Review
The Hedgehog (HH) signalling pathway is one of the major pathways controlling cell differentiation and proliferation during human development. This pathway is complex, with HH function influenced by inhibitors, promotors, interactions with other signalling pathways, and non-genetic and cellular factors. Many aspects of this pathway are not yet clarified. The main features of Sonic Hedgehog (SHH) signalling are discussed in relation to its function in human development. The possible role of SHH will be considered using examples of holoprosencephaly and short-rib polydactyly (SRP) syndromes. In these syndromes, there is wide variability in phenotype even with the same genetic mutation, so that other factors must influence the outcome. mutations were the first identified genetic causes of holoprosencephaly, but many other genes and environmental factors can cause malformations in the holoprosencephaly spectrum. Many patients with SRP have genetic defects affecting primary cilia, structures found on most mammalian cells which are thought to be necessary for canonical HH signal transduction. Although SHH signalling is affected in both these genetic conditions, there is little overlap in phenotype. Possible explanations will be canvassed, using data from published human and animal studies. Implications for the understanding of SHH signalling in humans will be discussed.
Topics: Animals; Cilia; Ciliopathies; Hedgehog Proteins; Holoprosencephaly; Humans; Short Rib-Polydactyly Syndrome; Signal Transduction
PubMed: 34576017
DOI: 10.3390/ijms22189854 -
Proceedings of the National Academy of... Sep 2021Skeletal ciliopathies (e.g., Jeune syndrome, short rib polydactyly syndrome, and Sensenbrenner syndrome) are frequently associated with nephronophthisis-like cystic...
Skeletal ciliopathies (e.g., Jeune syndrome, short rib polydactyly syndrome, and Sensenbrenner syndrome) are frequently associated with nephronophthisis-like cystic kidney disease and other organ manifestations. Despite recent progress in genetic mapping of causative loci, a common molecular mechanism of cartilage defects and cystic kidneys has remained elusive. Targeting two ciliary chondrodysplasia loci ( and ) by CRISPR/Cas9 mutagenesis, we established models for skeletal ciliopathies in Froglets exhibited severe limb deformities, polydactyly, and cystic kidneys, closely matching the phenotype of affected patients. A data mining-based in silico screen found to be related to known skeletal ciliopathy genes. CRISPR/Cas9 targeting replicated limb malformations and renal cysts identical to the models of established disease genes. Loss of Ttc30a impaired embryonic renal excretion and ciliogenesis because of altered posttranslational tubulin acetylation, glycylation, and defective axoneme compartmentalization. transcripts are enriched in chondrocytes and osteocytes of single-cell RNA-sequenced embryonic mouse limbs. We identify TTC30A/B as an essential node in the network of ciliary chondrodysplasia and nephronophthisis-like disease proteins and suggest that tubulin modifications and cilia segmentation contribute to skeletal and renal ciliopathy manifestations of ciliopathies in a cell type-specific manner. These findings have implications for potential therapeutic strategies.
Topics: Animals; Bone and Bones; Ciliopathies; Craniosynostoses; Cytoskeletal Proteins; Disease Models, Animal; Ectodermal Dysplasia; Embryo, Nonmammalian; Musculoskeletal Abnormalities; Phenotype; Polycystic Kidney Diseases; Tubulin; Xenopus laevis
PubMed: 34548398
DOI: 10.1073/pnas.2106770118 -
FASEB Journal : Official Publication of... Jan 2021Enzymatic control of lipid homeostasis in the cell is a vital element in the complex organization of life. Phosphatidylserine (PS) is an essential anionic phospholipid... (Review)
Review
Enzymatic control of lipid homeostasis in the cell is a vital element in the complex organization of life. Phosphatidylserine (PS) is an essential anionic phospholipid of cell membranes, and conducts numerous roles for their structural and functional integrity. In mammalian cells, two distinct enzymes phosphatidylserine synthases-1 (PSS1) and -2 (PSS2) in the mitochondria-associated membrane (MAM) in the ER perform de novo synthesis of PS. It is based on base-exchange reactions of the preexisting dominant phospholipids phosphatidylcholine (PC) and phosphatidylethanolamine (PE). While PSS2 specifically catalyzes the reaction "PE → PS," whether or not PSS1 is responsible for the same reaction along with the reaction "PC → PS" remains unsettled despite its fundamental impact on the major stoichiometry. We propose here that a key but the only report that appeared to have put scientists on hold for decades in answering to this issue may be viewed consistently with other available research reports; PSS1 utilizes the two dominant phospholipid classes at a similar intrinsic rate. In this review, we discuss the issue in view of the current information for the enzyme machineries, membrane structure and dynamics, intracellular network of lipid transport, and PS synthesis in health and disease. Resolution of the pending issue is thus critical in advancing our understanding of roles of the essential anionic lipid in biology, health, and disease.
Topics: Animals; Homeostasis; Humans; Lipid Metabolism; Mitochondrial Membranes; Nitrogenous Group Transferases; Phosphatidylethanolamines; Phosphatidylserines
PubMed: 33205488
DOI: 10.1096/fj.202001802R