Saul-Wilson Syndrome Missense Allele Does Not Show Obvious Golgi Defects in a C. elegans Model.
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ABSTRACT:
SUBMITTER: Zafra I
PROVIDER: S-EPMC7933980 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Saul-Wilson syndrome (SWS) is a rare autosomal recessive disorder characterized by microcephalic primordial dwarfism, spondyloepimetaphyseal dysplasia, characteristic facial findings, clubfoot, brachydactyly, bilateral cataracts, and hearing loss. Recently, recurrent mutations in COG4, encoding a component of the Conserved Oligomeric Golgi (COG) complex, were identified. We created detailed growth curves for stature, weight, and head circumference, as well as weight-for-length and weight velocity charts for younger children, derived from hundreds of data points obtained by retrospective chart review from 14 individuals with molecularly-confirmed SWS. In addition, we performed statistical comparisons of height-for-age model fits before and after initiation of growth hormone supplementation, and found that this therapy does not appear to influence height in individuals with SWS. We hope that these charts will represent valuable tools for clinicians, both in assessing whether SWS seems an appropriate diagnosis, as well as to monitor growth of affected individuals. In particular, we hope that our detailed growth characterization will reduce morbidity resulting from unnecessarily aggressive nutritional interventions by well-intentioned physicians trying to promote weight gain, an unrealistic goal in this genetically-determined cause of primordial dwarfism.
| S-EPMC9016779 | biostudies-literature
Project description:PurposeFour patients with Saul-Wilson syndrome were reported between 1982 and 1994, but no additional individuals were described until 2018, when the molecular etiology of the disease was elucidated. Hence, the clinical phenotype of the disease remains poorly defined. We address this shortcoming by providing a detailed characterization of its phenotype.MethodsRetrospective chart reviews were performed and primary radiographs assessed for all 14 individuals. Four individuals underwent detailed ophthalmologic examination by the same physician. Two individuals underwent gynecologic evaluation. Z-scores for height, weight, head circumference and body mass index were calculated at different ages.ResultsAll patients exhibited short stature, with sharp decline from the mean within the first months of life, and a final height Z-score between -4 and -8.5 standard deviations. The facial and radiographic features evolved over time. Intermittent neutropenia was frequently observed. Novel findings included elevation of liver transaminases, skeletal fragility, rod-cone dystrophy, and cystic macular changes.ConclusionsSaul-Wilson syndrome presents a remarkably uniform phenotype, and the comprehensive description of our cohort allows for improved understanding of the long-term morbidity of the condition, establishment of follow-up recommendations for affected individuals, and documentation of the natural history into adulthood for comparison with treated patients, when therapeutics become available.
| S-EPMC7205587 | biostudies-literature
Project description:Saul Wilson syndrome (SWS) is a rare congenital syndrome characterized by a variety of symptoms, mostly skeletal changes. Saul and Wilson were the first to describe children with extremely short stature and craniofacial dysmorphism. We present a case of a 15-years-old boy with clinical and radiological characteristics of SWS. Genetic examination identified a pathogenic heterozygous variant in the COG4 gene. Magnetic resonance imaging revealed a critical stenosis of the cranio-cervical junction (CCJ) which required surgical treatment to attempt sufficient neurological decompression. The patient underwent decompression of CCJ under general anesthesia. There was no significant radiological and clinical improvement during the postoperative period. SWS is presented as an extremely rare congenital disease in children. The clinical condition of our patient confined surgical possibilities, therefore further treatment in such patients should be appropriately evaluated.
| S-EPMC9031859 | biostudies-literature
Project description:Saul-Wilson syndrome is a rare skeletal dysplasia caused by a heterozygous mutation in COG4 (p.G516R). Our previous study showed that this mutation affected glycosylation of proteoglycans and disturbed chondrocyte elongation and intercalation in zebrafish embryos expressing the COG4p.G516R variant. How this mutation causes chondrocyte deficiencies remain unsolved. To analyze a disease-relevant cell type, COG4p.G516R variant was generated by CRISPR knock-in technique in the chondrosarcoma cell line SW1353 to study chondrocyte differentiation and protein secretion. COG4p.G516R cells display impaired protein trafficking and altered COG complex size, similar to SWS-derived fibroblasts. Both SW1353 and HEK293T cells carrying COG4p.G516R showed very modest, cell-type dependent changes in N-glycans. Using 3D culture methods, we found that cells carrying the COG4p.G516R variant made smaller spheroids and had increased apoptosis, indicating impaired in vitro chondrogenesis. Adding WT cells or their conditioned medium reduced cell death and increased spheroid sizes of COG4p.G516R mutant cells, suggesting a deficiency in secreted matrix components. Mass spectrometry-based secretome analysis showed selectively impaired protein secretion, including MMP13 and IGFBP7 which are involved in chondrogenesis and osteogenesis. We verified reduced expression of chondrogenic differentiation markers, MMP13 and COL10A1 and delayed response to BMP2 in COG4p.G516R mutant cells. Collectively, our results show that the Saul-Wilson syndrome COG4p.G516R variant selectively affects the secretion of multiple proteins, especially in chondrocyte-like cells which could further cause pleiotropic defects including hampering long bone growth in SWS individuals.
| S-EPMC9649697 | biostudies-literature
Project description:Saul-Wilson syndrome (SWS) is a rare skeletal dysplasia often presents with features such as a distinct facial phenotype, cataracts, short stature, clubfoot deformities, and microcephaly. We have previously identified that the causative mutation in SWS is a heterozygous, dominant variant (p.G516R) in COG4. COG4 is a Golgi-associated protein which plays important roles in protein trafficking. We further showed that the mutation impacts glycosylation of proteoglycans and disturbs chondrocyte elongation and intercalation in zebrafish embryos expressing COG4p.G516R variant. These effects could be partially rescued by adding wild type cells or their conditioned medium, implicating secretion anomalies associated with COG4p.G516R variant. We have conducted proteomic analysis of the conditioned medium from chondrocyte-like cells (SW1353) expressing COG4p.G516R variant and compared these to wild type SW1353 cells and a knockout of COG4 in these cells. 4,4438 proteins were identified and quantified and comparative analysis was performed. We utilized 3D cultures for performing secretome analysis to investigate the specific changes caused by p.G516R variant compared to WT and COG4-KO.
2023-03-11 | PXD036151 | Pride
Project description:The conserved oligomeric Golgi (COG) complex is involved in intracellular vesicular transport, and is composed of eight subunits distributed in two lobes, lobe A (COG1-4) and lobe B (COG5-8). We describe fourteen individuals with Saul-Wilson syndrome, a rare form of primordial dwarfism with characteristic facial and radiographic features. All affected subjects harbored heterozygous de novo variants in COG4, giving rise to the same recurrent amino acid substitution (p.Gly516Arg). Affected individuals' fibroblasts, whose COG4 mRNA and protein were not decreased, exhibited delayed anterograde vesicular trafficking from the ER to the Golgi and accelerated retrograde vesicular recycling from the Golgi to the ER. This altered steady-state equilibrium led to a decrease in Golgi volume, as well as morphologic abnormalities with collapse of the Golgi stacks. Despite these abnormalities of the Golgi apparatus, protein glycosylation in sera and fibroblasts from affected subjects was not notably altered, but decorin, a proteoglycan secreted into the extracellular matrix, showed altered Golgi-dependent glycosylation. In summary, we define a specific heterozygous COG4 substitution as the molecular basis of Saul-Wilson syndrome, a rare skeletal dysplasia distinct from biallelic COG4-CDG.
| S-EPMC6174323 | biostudies-literature
Project description:Lowe syndrome is an X-linked condition characterized by congenital cataracts, neurological abnormalities and kidney malfunction. This lethal disease is caused by mutations in the OCRL1 gene, which encodes for the phosphatidylinositol 5-phosphatase Ocrl1. While in the past decade we witnessed substantial progress in the identification and characterization of LS patient cellular phenotypes, many of these studies have been performed in knocked-down cell lines or patient's cells from accessible cell types such as skin fibroblasts, and not from the organs affected. This is partially due to the limited accessibility of patient cells from eyes, brain and kidneys. Here we report the preparation of induced pluripotent stem cells (iPSCs) from patient skin fibroblasts and their reprogramming into kidney cells. These reprogrammed kidney cells displayed primary cilia assembly defects similar to those described previously in cell lines. Additionally, the transcription factor and cap mesenchyme marker Six2 was substantially retained in the Golgi complex and the functional nuclear-localized fraction was reduced. These results were confirmed using different batches of differentiated cells from different iPSC colonies and by the use of the human proximal tubule kidney cell line HK2. Indeed, OCRL1 KO led to both ciliogenesis defects and Six2 retention in the Golgi complex. In agreement with Six2's role in the suppression of ductal kidney lineages, cells from this pedigree were over-represented among patient kidney-reprogrammed cells. We speculate that this diminished efficacy to produce cap mesenchyme cells would cause LS patients to have difficulties in replenishing senescent or damaged cells derived from this lineage, particularly proximal tubule cells, leading to pathological scenarios such as tubular atrophy.
| S-EPMC5812626 | biostudies-literature
Project description:Saul-Wilson syndrome (SWS) is a rare, skeletal dysplasia with progeroid appearance and primordial dwarfism. It is caused by a heterozygous, dominant variant (p.G516R) in COG4, a subunit of the conserved oligomeric Golgi (COG) complex involved in intracellular vesicular transport. Our previous work has shown the intracellular disturbances caused by this mutation; however, the pathological mechanism of SWS needs further investigation. We sought to understand the molecular mechanism of specific aspects of the SWS phenotype by analyzing SWS-derived fibroblasts and zebrafish embryos expressing this dominant variant. SWS fibroblasts accumulate glypicans, a group of heparan sulfate proteoglycans (HSPGs) critical for growth and bone development through multiple signaling pathways. Consistently, we find that glypicans are increased in zebrafish embryos expressing the COG4 p.G516R variant. These animals show phenotypes consistent with convergent extension (CE) defects during gastrulation, shortened body length, and malformed jaw cartilage chondrocyte intercalation at larval stages. Since non-canonical Wnt signaling was shown in zebrafish to be related to the regulation of these processes by glypican 4, we assessed wnt levels and found a selective increase of wnt4 transcripts in the presence of COG4 p.G516R . Moreover, overexpression of wnt4 mRNA phenocopies these developmental defects. LGK974, an inhibitor of Wnt signaling, corrects the shortened body length at low concentrations but amplifies it at slightly higher concentrations. WNT4 and the non-canonical Wnt signaling component phospho-JNK are also elevated in cultured SWS-derived fibroblasts. Similar results from SWS cell lines and zebrafish point to altered non-canonical Wnt signaling as one possible mechanism underlying SWS pathology.
| S-EPMC8476873 | biostudies-literature
Project description:From a screen for meiotic Caenorhabditis elegans mutants based on high incidence of males, we identified a novel gene, him-19, with multiple functions in prophase of meiosis I. Mutant him-19(jf6) animals show a reduction in pairing of homologous chromosomes and subsequent bivalent formation. Consistently, synaptonemal complex formation is spatially restricted and possibly involves nonhomologous chromosomes. Also, foci of the recombination protein RAD-51 occur delayed or cease altogether. Ultimately, mutation of him-19 leads to chromosome missegregation and reduced offspring viability. The observed defects suggest that HIM-19 is important for both homology recognition and formation of meiotic DNA double-strand breaks. It therefore seems to be engaged in an early meiotic event, resembling in this respect the regulator kinase CHK-2. Most astonishingly, him-19(jf6) hermaphrodites display worsening of phenotypes with increasing age, whereas defects are more severe in female than in male meiosis. This finding is consistent with depletion of a him-19-dependent factor during the production of oocytes. Further characterization of him-19 could contribute to our understanding of age-dependent meiotic defects in humans.
| S-EPMC2836969 | biostudies-literature
Project description:Mowat-Wilson syndrome (MWS) is a multiple congenital anomaly syndrome characterized by a distinct facial phenotype (high forehead, frontal bossing, large eyebrows, medially flaring and sparse in the middle part, hypertelorism, deep set but large eyes, large and uplifted ear lobes, with a central depression, saddle nose with prominent rounded nasal tip, prominent columella, open mouth, with M-shaped upper lip, frequent smiling, and a prominent but narrow and triangular pointed chin), moderate-to-severe intellectual deficiency, epilepsy and variable congenital malformations including Hirschsprung disease (HSCR), genitourinary anomalies (in particular hypospadias in males), congenital heart defects, agenesis of the corpus callosum and eye anomalies. The prevalence of MWS is currently unknown, but 171 patients have been reported so far. It seems probable that MWS is under-diagnosed, particularly in patients without HSCR. MWS is caused by heterozygous mutations or deletions in the Zinc finger E-box-binding homeobox 2 gene, ZEB2, previously called ZFHX1B (SIP1). To date, over 100 deletions/mutations have been reported in patients with a typical phenotype; they are frequently whole gene deletions or truncating mutations, suggesting that haploinsufficiency is the main pathological mechanism. Studies of genotype-phenotype analysis show that facial gestalt and delayed psychomotor development are constant clinical features, while the frequent and severe congenital malformations are variable. In a small number of patients, unusual mutations can lead to an atypical phenotype. The facial phenotype is particularly important for the initial clinical diagnosis and provides the hallmark warranting ZEB2 mutational analysis, even in the absence of HSCR. The majority of MWS cases reported so far were sporadic, therefore the recurrence risk is low. Nevertheless, rare cases of sibling recurrence have been observed. Congenital malformations and seizures require precocious clinical investigation with intervention of several specialists (including neonatologists and pediatricians). Psychomotor development is delayed in all patients, therefore rehabilitation (physical therapy, psychomotor and speech therapy) should be started as soon as possible.
| S-EPMC2174447 | biostudies-literature