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Molecular Genetics & Genomic Medicine Jun 2024Serine residues in the protein backbone of heavily glycosylated proteoglycans are bound to glycosaminoglycans through a tetrasaccharide linker. UXS1 encodes...
BACKGROUND
Serine residues in the protein backbone of heavily glycosylated proteoglycans are bound to glycosaminoglycans through a tetrasaccharide linker. UXS1 encodes UDP-glucuronate decarboxylase 1, which catalyzes synthesis of UDP-xylose, the donor of the first building block in the linker. Defects in other enzymes involved in formation of the tetrasaccharide linker cause so-called linkeropathies, characterized by short stature, radio-ulnar synostosis, decreased bone density, congenital contractures, dislocations, and more.
METHODS
Whole exome sequencing was performed in a father and son who presented with a mild skeletal dysplasia, as well as the father's unaffected parents. Wild-type and mutant UXS1 were recombinantly expressed in Escherichia coli and purified. Enzyme activity was evaluated by LC-MS/MS. In vivo effects were studied using HeparinRed assay and metabolomics.
RESULTS
The son had short long bones, normal epiphysis, and subtle metaphyseal changes especially in his legs. The likely pathogenic heterozygous variant NM_001253875.1(UXS1):c.557T>A p.(Ile186Asn) detected in the son was de novo in the father. Purified Ile186Asn-UXS1, in contrast to the wild-type, was not able to convert UDP-glucuronic acid to UDP-xylose. Plasma glycosaminoglycan levels were decreased in both son and father.
CONCLUSION
This is the first report linking UXS1 to short-limbed short stature in humans.
Topics: Humans; Male; Dwarfism; Carboxy-Lyases; Alleles; Phenotype; Mutation; Adult; Pedigree
PubMed: 38860481
DOI: 10.1002/mgg3.2472 -
DNA Research : An International Journal... Jun 2024Micro-Tom is a cultivar of tomato (Solanum lycopersicum), which is known as a major crop and model plant in Solanaceae. Micro-Tom has phenotypic traits such as dwarfism,...
Micro-Tom is a cultivar of tomato (Solanum lycopersicum), which is known as a major crop and model plant in Solanaceae. Micro-Tom has phenotypic traits such as dwarfism, and substantial EMS-mutagenized lines have been reported. After Micro-Tom was generated in Florida, USA, it was distributed to research institutes worldwide and used as a genetic resource. In Japan, the Micro-Tom lines have been genetically fixed; currently three lines have been re-distributed from three institutes, but many phenotypes among the lines have been observed. We have determined the genome sequence de novo of the Micro-Tom KDRI line, one of the Micro-Tom lines distributed from Kazusa DNA Research Institute (KDRI) in Japan, and have built chromosome-scale pseudomolecules. Genotypes among six Micro-Tom lines, including three in Japan, one in the United States, one in France, and one in Brazil showed phenotypic alternation. Here, we unveiled the swift emergence of genetic diversity in both phenotypes and genotypes within the Micro-Tom genome sequence during its propagation. These findings offer valuable insights crucial for the management of bioresources.
PubMed: 38845356
DOI: 10.1093/dnares/dsae016 -
Proceedings of the National Academy of... Jun 2024Transcription is extremely important for cellular processes but can be hindered by RNA polymerase II (RNAPII) pausing and stalling. Cockayne syndrome protein B (CSB)...
Transcription is extremely important for cellular processes but can be hindered by RNA polymerase II (RNAPII) pausing and stalling. Cockayne syndrome protein B (CSB) promotes the progression of paused RNAPII or initiates transcription-coupled nucleotide excision repair (TC-NER) to remove stalled RNAPII. However, the specific mechanism by which CSB initiates TC-NER upon damage remains unclear. In this study, we identified the indispensable role of the ARK2N-CK2 complex in the CSB-mediated initiation of TC-NER. The ARK2N-CK2 complex is recruited to damage sites through CSB and then phosphorylates CSB. Phosphorylation of CSB enhances its binding to stalled RNAPII, prolonging the association of CSB with chromatin and promoting CSA-mediated ubiquitination of stalled RNAPII. Consistent with this finding, mice exhibit a phenotype resembling Cockayne syndrome. These findings shed light on the pivotal role of the ARK2N-CK2 complex in governing the fate of RNAPII through CSB, bridging a critical gap necessary for initiating TC-NER.
Topics: DNA Repair Enzymes; RNA Polymerase II; Poly-ADP-Ribose Binding Proteins; Humans; Animals; Mice; DNA Repair; DNA Helicases; Cockayne Syndrome; Transcription, Genetic; Phosphorylation; Casein Kinase II; Mice, Knockout; DNA Damage; ATPases Associated with Diverse Cellular Activities; Chromatin; Ubiquitination; Excision Repair
PubMed: 38843184
DOI: 10.1073/pnas.2404383121 -
Translational Pediatrics May 2024Alport syndrome (AS) is a rare progressive hereditary kidney disease that is clinically principally associated with hematuria, proteinuria, and progressive renal...
BACKGROUND
Alport syndrome (AS) is a rare progressive hereditary kidney disease that is clinically principally associated with hematuria, proteinuria, and progressive renal dysfunction. This condition not only impairs renal function but also potentially affects auditory and ocular health, significantly impacting the patient's quality of life.
CASE DESCRIPTION
This article reports a young girl with AS, combined with dwarfism attributable to growth hormone (GH) deficiency, diagnosed at Wenzhou People's Hospital in 2019. The clinical data and diagnostic steps were retrospectively analyzed. Genetic testing showed that she carried a new mutation in the gene, c.2317_2318delAG (p.R773Gfs*14), classified as "pathogenic" under the criteria of the American College of Medical Genetics and Genomics (ACMG), confirming her AS diagnosis. Significantly, the patient's height was more than two standard deviations (SDs) below the average for children of her race, sex, and age. The peak GH level post-stimulation was below 5 ng/mL, coupled with a growth rate of less than 5 cm/year, leading to the diagnosis of GH deficiency. Consequently, recombinant human GH (rhGH) therapy was initiated.
CONCLUSIONS
After a year of rhGH treatment, we observed a notable increase in her height, without any adverse effects like elevated intracranial pressure, hypothyroidism, or worsening kidney function.
PubMed: 38840691
DOI: 10.21037/tp-23-569 -
Clinical Epigenetics Jun 2024Silver-Russell syndrome (SRS) is a representative imprinting disorder characterized by pre- and postnatal growth failure. We encountered two Japanese SRS cases with a de... (Review)
Review
Silver-Russell syndrome (SRS) is a representative imprinting disorder characterized by pre- and postnatal growth failure. We encountered two Japanese SRS cases with a de novo pathogenic frameshift variant of HMGA2 (NM_003483.6:c.138_141delinsCT, p.(Lys46Asnfs*16)) and a de novo ~ 3.4 Mb microdeletion at 12q14.2-q15 involving HMGA2, respectively. Furthermore, we compared clinical features in previously reported patients with various genetic conditions leading to compromised IGF2 expression, i.e., HMGA2 aberrations, PLAG1 aberrations, IGF2 aberrations, and H19/IGF2:IG-DMR epimutations (hypomethylations). The results provide further support for HMGA2 being involved in the development of SRS and imply some characteristic features in patients with HMGA2 aberrations.
Topics: Humans; Silver-Russell Syndrome; HMGA2 Protein; Male; Female; Frameshift Mutation; Japan; Genomic Imprinting; Infant; Insulin-Like Growth Factor II; DNA Methylation; Chromosomes, Human, Pair 12
PubMed: 38840187
DOI: 10.1186/s13148-024-01688-w -
Asian Journal of Endoscopic Surgery Jul 2024Thanatophoric dysplasia (TD) is a rare and severe type of skeletal dysplasia. Typical clinical findings include macrocephaly, shortening of the four limbs,...
Thanatophoric dysplasia (TD) is a rare and severe type of skeletal dysplasia. Typical clinical findings include macrocephaly, shortening of the four limbs, underdeveloped lungs, and thoracic hypoplasia. Neonates with TD develop severe respiratory problems due to thoracic hypoplasia and require respiratory management for survival. Despite the resolution of respiratory problems, long-term survival cases are rare. Previous studies have reported that surgical procedures in patients with TD are limited to those necessary for survival, including tracheostomy, laminectomy, and ventricular shunt. A 1-year-old boy with TD was treated with laparoscopic herniorrhaphy. To the best of our knowledge, this is the first report of TD treated with laparoscopic procedure.
Topics: Humans; Male; Laparoscopy; Hernia, Inguinal; Herniorrhaphy; Thanatophoric Dysplasia; Infant
PubMed: 38839103
DOI: 10.1111/ases.13325 -
Clinical Genetics Jun 2024Microcephalic osteodysplastic primordial dwarfism type I (MOPDI) is a very rare and severe autosomal recessive disorder characterized by marked intrauterine growth...
Microcephalic osteodysplastic primordial dwarfism type I (MOPDI) is a very rare and severe autosomal recessive disorder characterized by marked intrauterine growth retardation, skeletal dysplasia, microcephaly and brain malformations. MOPDI is caused by biallelic mutations in RNU4ATAC, a non-coding gene involved in U12-type splicing of 1% of the introns in the genome, which are recognized by their specific splicing consensus sequences. Here, we describe a unique observation of immunodeficiency in twin sisters with mild MOPDI, who harbor a novel n.108_126del mutation, encompassing part of the U4atac snRNA 3' stem-loop and Sm protein binding site, and the previously reported n.111G>A mutation. Interestingly, both twin sisters show mild B-cell anomalies, including low naive B-cell counts and increased memory B-cell and plasmablasts counts, suggesting partial and transitory blockage of B-cell maturation and/or excessive activation of naive B-cells. Hence, the localization of a mutation in stem II of U4atac snRNA, as observed in another RNU4ATAC-opathy with immunodeficiency, that is, Roifman syndrome (RFMN), is not required for the occurrence of an immune deficiency. Finally, we emphasize the importance of considering immunodeficiency in MOPDI management to reduce the risk of serious infectious episodes.
PubMed: 38837402
DOI: 10.1111/cge.14571 -
Journal of Veterinary Diagnostic... Jun 2024Measures of manganese (Mn) status in cattle vary among studies, and no single criterion accurately predicts or diagnoses Mn deficiency and pathologic outcomes. Mn...
Measures of manganese (Mn) status in cattle vary among studies, and no single criterion accurately predicts or diagnoses Mn deficiency and pathologic outcomes. Mn deficiency causes congenital joint laxity and dwarfism (CJLD) when total dietary intake is <20 ppm Mn dry matter (DM) for most of the pregnancy. However, the recommended dietary intake of 40 ppm DM can also result in clinical Mn deficiency. Some studies have found that CJLD occurs in calves from cows fed red clover or silage but not in calves from cows fed hay. The concentration of Mn in the liver is the best indicator of Mn status in neonates and adults but cannot be interpreted in fetuses. Serum, plasma, and whole blood concentrations of Mn are unreliable indicators of bovine Mn status. The primary objective of our report is to present evidence linking CJLD to a primary or secondary Mn deficiency. To predict and diagnose Mn deficiency in cattle, we propose using a combination of clinical signs, dietary Mn, liver Mn at birth and beyond, positive response to Mn supplementation or the replacement of silage with other forages, and ruling out other causes of malformations. By following these recommendations, we expect that CJLD and gestational death will decrease as hepatic Mn concentrations increase at birth. Many publications we reviewed are not statistically sound, and future research should include a statistician from the initial discussions of the study through the final publication.
PubMed: 38835276
DOI: 10.1177/10406387241257672 -
Nature Communications Jun 2024Cohesin mediates sister chromatid cohesion to enable chromosome segregation and DNA damage repair. To perform these functions, cohesin needs to be protected from WAPL,...
Cohesin mediates sister chromatid cohesion to enable chromosome segregation and DNA damage repair. To perform these functions, cohesin needs to be protected from WAPL, which otherwise releases cohesin from DNA. It has been proposed that cohesin is protected from WAPL by SORORIN. However, in vivo evidence for this antagonism is missing and SORORIN is only known to exist in vertebrates and insects. It is therefore unknown how important and widespread SORORIN's functions are. Here we report the identification of SORORIN orthologs in Schizosaccharomyces pombe (Sor1) and Arabidopsis thaliana (AtSORORIN). sor1Δ mutants display cohesion defects, which are partially alleviated by wpl1Δ. Atsororin mutant plants display dwarfism, tissue specific cohesion defects and chromosome mis-segregation. Furthermore, Atsororin mutant plants are sterile and separate sister chromatids prematurely at anaphase I. The somatic, but not the meiotic deficiencies can be alleviated by loss of WAPL. These results provide in vivo evidence for SORORIN antagonizing WAPL, reveal that SORORIN is present in organisms beyond the animal kingdom and indicate that it has acquired tissue specific functions in plants.
Topics: Arabidopsis; Cell Cycle Proteins; Schizosaccharomyces pombe Proteins; Arabidopsis Proteins; Chromosomal Proteins, Non-Histone; Schizosaccharomyces; Cohesins; Chromosome Segregation; Mutation; Chromatids; Evolution, Molecular; Meiosis
PubMed: 38830897
DOI: 10.1038/s41467-024-49178-0 -
Clinical Dysmorphology Jul 2024Silver-Russell syndrome (SRS) is a well-known syndrome but with heterogeneous etiologies. We present the case of a child with severe SRS-like features resulting from a...
Silver-Russell syndrome (SRS) is a well-known syndrome but with heterogeneous etiologies. We present the case of a child with severe SRS-like features resulting from a complex rearrangement of chromosome 11 inherited from his mother. We studied the index case with karyotyping, MS-MLPA and molecular karyotyping. The mother was studied with karyotyping and subtelomeric FISH. We found a child with marked developmental delay and fatal outcome due to failure to thrive, carrying an 11p15 duplication and an 11q25 deletion of maternal origin. We discovered that the mother was a carrier of a pericentric inversion of chromosome 11, with a history of recurrence in other family members who had severe growth retardation and early death. To our knowledge, no similar SRS-like cases have been described in the literature. This report supports the importance of identification the causative genetic mechanism in SRS-like individuals with duplication in 11p15 region due to high risk of recurrence and to provide an appropriate genetic counseling to the family.
Topics: Humans; Chromosome Inversion; Chromosomes, Human, Pair 11; In Situ Hybridization, Fluorescence; Karyotyping; Pedigree; Phenotype; Silver-Russell Syndrome
PubMed: 38818816
DOI: 10.1097/MCD.0000000000000483