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1.
Am J Med Genet A ; 185(11): 3510-3516, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34472180

RESUMO

Mucopolysaccharidosis type IVA (OMIM 253000) is an autosomal recessive disorder caused by defective activity of the N-acetylgalactosamine 6-sulfatase (GALNS) enzyme. In 2014, enzyme replacement therapy (ERT) using recombinant human GALNS became available for affected patients. There is a limited number of studies to date that have explored the effect of ERT in infancy and there is also a lack of data assessing the effect of ERT in systems other than the skeletal. Here, we report on the effect of ERT in the youngest pair of siblings treated to date: Patient A, currently 4 years old, who started treatment at the age of 5 months; and Patient B, currently 3 years old, who started treatment at 58 days of life. Moreover, we investigate the effect of early ERT on the cardiovascular system. Our results show that, even when ERT is started before 2 months of age, it cannot fully prevent disease progression. As for the effect of ERT on the cardiovascular system, our preliminary results suggest that early treatment might play a role in preserving a normal left ventricular mass index in affected patients at least up to 1 year, but further observation over time will be required. Overall, this report shows that early diagnosis remains crucial and that prompt initiation of ERT has limited effect in slowing progression of the skeletal phenotype, thus confirming the need for new therapeutic approaches that target the skeletal system in affected patients.


Assuntos
Condroitina Sulfatases/genética , Terapia de Reposição de Enzimas , Mucopolissacaridose IV/tratamento farmacológico , Pré-Escolar , Humanos , Lactente , Masculino , Mucopolissacaridose IV/genética , Mucopolissacaridose IV/patologia , Irmãos
2.
Am J Med Genet A ; 179(5): 852-856, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30806031

RESUMO

Cornelia de Lange syndrome (CdLS) is an autosomal dominant genetic disorder caused by pathogenic variants in NIPBL, RAD21, SMC3, HDAC8, or SMC1A; all of which code for proteins that are components of, or interact with, the cohesin complex. Despite the identification of multiple genes associated with CdLS, over 25% of individuals strongly suspected to have CdLS have negative genetic testing, indicating that there are additional genes associated with the condition. HDAC2 codes for histone deacetylase 2 (HDAC2) and, like HDAC8, is a Class 1 histone deacetylase. We present a patient with a novel de novo variant in HDAC2 with many clinical features consistent with CdLS including severe developmental delay, limb abnormalities, congenital heart defect, cryptorchidism and hypoplastic genitalia, growth retardation, and characteristic craniofacial features. Although variants in HDAC2 are not currently associated with human disease, the variant identified in this patient is within a highly conserved amino acid residue and has not been observed in healthy populations. This information, along with the patient's clinical presentation and the functional similarity between the HDAC2 and HDAC8 proteins, suggests that HDAC2 should be further investigated as a candidate gene for CdLS or a CdLS-like syndrome.


Assuntos
Síndrome de Cornélia de Lange/diagnóstico , Síndrome de Cornélia de Lange/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Variação Genética , Histona Desacetilase 2/genética , Fenótipo , Pré-Escolar , Fácies , Humanos , Lactente , Imageamento por Ressonância Magnética , Masculino , Mutação , Radiografia
3.
Mol Genet Genomic Med ; 11(4): e2135, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36756677

RESUMO

BACKGROUND: Renal-hepatic-pancreatic dysplasia type 2 (RHPD2) is a rare condition that has been described in the literature disproportionately in perinatal losses. The main features of liver and kidney involvement are well described, with cardiac malformations and cardiomyopathy adding additional variation to the phenotype. Many patients reported are within larger cohorts of congenital anomalies of kidney and urinary tract (CAKUT) or liver failure, and with minimal phenotypic and clinical course data. METHODS: An independent series of phenotypes and prognosis was aggregated from the literature. In this literature review, we describe an additional patient with RHPD2, provide a clinical update on the oldest known living patient, and report the cumulative phenotypes from the existing published patients. RESULTS: With now examining the 17 known patients in the literature, 13 died within the perinatal period-pregnancy to one year of life. Of the four cases living past the first year of life, one case died at 5 years secondary to renal failure, the other at 30 months secondary to liver and kidney failure. Two are currently alive and well at one year and 13 years. Two cases have had transplantation with one resulting in long-term survival. CONCLUSIONS: These patients serve to expand the existing phenotype of RHPD2 as a perinatal lethal condition into a pediatric disorder with variable expressivity. Additionally, we introduce the consideration of transplantation and outcomes within this cohort and future patients.


Assuntos
Anormalidades Múltiplas , Sistema Urinário , Gravidez , Feminino , Humanos , Rim/anormalidades , Sistema Urinário/anormalidades , Fígado
4.
Dev Comp Immunol ; 87: 182-187, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29958850

RESUMO

Neonates of all species, including foals, are highly susceptible to infection, and neutrophils play a crucial role in innate immunity to infection. Evidence exists that neutrophils of neonatal foals are functionally deficient during the first weeks of life, including expression of cytokine genes such as IFNG. We hypothesized that postnatal epigenetic changes were likely to regulate the observed age-related changes in foal neutrophils. Using ChIP-Seq, we identified significant differences in trimethylated histone H3 lysine 4, an epigenetic modification associated with active promoters and enhancers, in neutrophils in foals at 30 days of age relative to 1 day of age. These chromatin changes were associated with genes implicated in immune responses and were consistent with age-related changes in neutrophil functional responses including ROS generation and IFN expression. Postnatal changes in epigenetic modifications suggest that environmentally-mediated cues help to promote maturation of neutrophil functional responses. Elucidating the environmental triggers and their signaling pathways could provide a means for improving innate immune responses of neonates to improve their ability to combat infectious diseases.


Assuntos
Epigênese Genética , Cavalos/genética , Neutrófilos/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Animais , Animais Recém-Nascidos , Citocinas/genética , Citocinas/imunologia , Histonas/metabolismo , Doenças dos Cavalos/genética , Doenças dos Cavalos/imunologia , Cavalos/crescimento & desenvolvimento , Cavalos/metabolismo , Imunidade Inata/genética , Imunidade Inata/imunologia , Lisina/metabolismo , Metilação , Neutrófilos/imunologia , Regiões Promotoras Genéticas/genética , Transdução de Sinais/genética , Transdução de Sinais/imunologia
5.
BMC Dev Biol ; 7: 121, 2007 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-17980035

RESUMO

BACKGROUND: Heparan sulfate proteoglycans modulate signaling by a variety of growth factors. The mammalian proteoglycan Perlecan binds and regulates signaling by Sonic Hedgehog, Fibroblast Growth Factors (FGFs), Vascular Endothelial Growth Factor (VEGF) and Platelet Derived Growth Factor (PDGF), among others, in contexts ranging from angiogenesis and cardiovascular development to cancer progression. The Drosophila Perlecan homolog trol has been shown to regulate the activity of Hedgehog and Branchless (an FGF homolog) to control the onset of stem cell proliferation in the developing brain during first instar. Here we extend analysis of trol mutant phenotypes to show that trol is required for a variety of developmental events and modulates signaling by multiple growth factors in different situations. RESULTS: Different mutations in trol allow developmental progression to varying extents, suggesting that trol is involved in multiple cell-fate and patterning decisions. Analysis of the initiation of neuroblast proliferation at second instar demonstrated that trol regulates this event by modulating signaling by Hedgehog and Branchless, as it does during first instar. Trol protein is distributed over the surface of the larval brain, near the regulated neuroblasts that reside on the cortical surface. Mutations in trol also decrease the number of circulating plasmatocytes. This is likely to be due to decreased expression of pointed, the response gene for VEGF/PDGF signaling that is required for plasmatocyte proliferation. Trol is found on plasmatocytes, where it could regulate VEGF/PDGF signaling. Finally, we show that in second instar brains but not third instar brain lobes and eye discs, mutations in trol affect signaling by Decapentaplegic (a Transforming Growth Factor family member), Wingless (a Wnt growth factor) and Hedgehog. CONCLUSION: These studies extend the known functions of the Drosophila Perlecan homolog trol in both developmental and signaling contexts. These studies also highlight the fact that Trol function is not dedicated to a single molecular mechanism, but is capable of regulating different growth factor pathways depending on the cell-type and event underway.


Assuntos
Drosophila/genética , Genes de Insetos , Proteoglicanas de Heparan Sulfato/genética , Transdução de Sinais/genética , Animais , Encéfalo/crescimento & desenvolvimento , Encéfalo/metabolismo , Contagem de Células , Proliferação de Células , Drosophila/crescimento & desenvolvimento , Drosophila/metabolismo , Proteínas de Drosophila/genética , Feminino , Gânglios dos Invertebrados/crescimento & desenvolvimento , Gânglios dos Invertebrados/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Proteínas Hedgehog/genética , Hemócitos/citologia , Hemócitos/metabolismo , Proteoglicanas de Heparan Sulfato/metabolismo , Larva/genética , Larva/crescimento & desenvolvimento , Larva/metabolismo , Masculino , Mutação , Fenótipo
6.
Epigenetics Chromatin ; 10: 27, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28515788

RESUMO

BACKGROUND: The ubiquitin protein E3A ligase gene (UBE3A) gene is imprinted with maternal-specific expression in neurons and biallelically expressed in all other cell types. Both loss-of-function and gain-of-function mutations affecting the dosage of UBE3A are associated with several neurodevelopmental syndromes and psychological conditions, suggesting that UBE3A is dosage-sensitive in the brain. The observation that loss of imprinting increases the dosage of UBE3A in brain further suggests that inactivation of the paternal UBE3A allele evolved as a dosage-regulating mechanism. To test this hypothesis, we examined UBE3A transcript and protein levels among cells, tissues, and species with different imprinting states of UBE3A. RESULTS: Overall, we found no correlation between the imprinting status and dosage of UBE3A. Importantly, we found that maternal Ube3a protein levels increase in step with decreasing paternal Ube3a protein levels during neurogenesis in mouse, fully compensating for loss of expression of the paternal Ube3a allele in neurons. CONCLUSIONS: Based on our findings, we propose that imprinting of UBE3A does not function to reduce the dosage of UBE3A in neurons but rather to regulate some other, as yet unknown, aspect of gene expression or protein function.


Assuntos
Dosagem de Genes/genética , Impressão Genômica , Herança Materna/genética , Ubiquitina-Proteína Ligases/genética , Alelos , Animais , Feminino , Regulação da Expressão Gênica , Camundongos , Neurogênese/genética , Neurônios/metabolismo , RNA Antissenso/genética , Ubiquitina-Proteína Ligases/biossíntese
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