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1.
Brain ; 146(11): 4766-4783, 2023 11 02.
Artículo en Inglés | MEDLINE | ID: mdl-37437211

RESUMEN

KPTN-related disorder is an autosomal recessive disorder associated with germline variants in KPTN (previously known as kaptin), a component of the mTOR regulatory complex KICSTOR. To gain further insights into the pathogenesis of KPTN-related disorder, we analysed mouse knockout and human stem cell KPTN loss-of-function models. Kptn -/- mice display many of the key KPTN-related disorder phenotypes, including brain overgrowth, behavioural abnormalities, and cognitive deficits. By assessment of affected individuals, we have identified widespread cognitive deficits (n = 6) and postnatal onset of brain overgrowth (n = 19). By analysing head size data from their parents (n = 24), we have identified a previously unrecognized KPTN dosage-sensitivity, resulting in increased head circumference in heterozygous carriers of pathogenic KPTN variants. Molecular and structural analysis of Kptn-/- mice revealed pathological changes, including differences in brain size, shape and cell numbers primarily due to abnormal postnatal brain development. Both the mouse and differentiated induced pluripotent stem cell models of the disorder display transcriptional and biochemical evidence for altered mTOR pathway signalling, supporting the role of KPTN in regulating mTORC1. By treatment in our KPTN mouse model, we found that the increased mTOR signalling downstream of KPTN is rapamycin sensitive, highlighting possible therapeutic avenues with currently available mTOR inhibitors. These findings place KPTN-related disorder in the broader group of mTORC1-related disorders affecting brain structure, cognitive function and network integrity.


Asunto(s)
Transducción de Señal , Serina-Treonina Quinasas TOR , Humanos , Animales , Ratones , Transducción de Señal/genética , Serina-Treonina Quinasas TOR/metabolismo , Encéfalo/metabolismo , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Cognición , Proteínas de Microfilamentos/genética
2.
J Clin Immunol ; 40(2): 321-328, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-31903518

RESUMEN

Cartilage-hair hypoplasia (CHH) is an autosomal recessive, short limb skeletal dysplasia with a variable immunologic phenotype. The spectrum of immune function ranges from clinically normal to severe combined immunodeficiency (SCID). Multiple studies have shown that abnormal immune parameters may not predict severe outcomes. Newborn screening (NBS) using T cell receptor excision circle (TREC) assay can now effectively identify infants with severe T cell deficiency who are at risk for SCID. NBS has allowed for cost-effective identification of patients with SCID and improved outcomes with hematopoietic stem cell transplant (HSCT). Ohio reports two abnormal TREC results: decreased and absent TREC. This study evaluated the laboratory and clinical differences in eight Amish patients with CHH with an abnormal TREC result on the NBS. There were four patients with absent TREC and four patients with decreased TREC. The absent TREC patients had lower CD3, CD4, naïve CD4, CD8 cells, and phytohemagglutinin (PHA)-induced lymphocyte proliferation. Three patients with absent TREC were diagnosed with SCID and two underwent successful HSCT. Patients with absent TREC experienced more CHH-related morbidity including anemia requiring transfusion, Hirschsprung's disease, and failure to thrive. No patients with decreased TREC required HSCT. Our study indicates that CHH patients with absent TREC tend to have more severe immunological and clinical phenotype than patients with decreased TREC. Confirmation of these trends in a larger group would guide providers and parents in a timely referral for HSCT, or cost-effective surveillance monitoring of children with a life-threatening illness.


Asunto(s)
Amish , Patología Molecular/métodos , Receptores de Antígenos de Linfocitos T/genética , Inmunodeficiencia Combinada Grave/diagnóstico , Linfocitos T/inmunología , Síndromes de Tricotiodistrofia/diagnóstico , Células Cultivadas , Preescolar , Estudios de Cohortes , Estudios de Seguimiento , Trasplante de Células Madre Hematopoyéticas , Humanos , Lactante , Recién Nacido , Activación de Linfocitos , Tamizaje Neonatal , Pronóstico , Inmunodeficiencia Combinada Grave/genética , Resultado del Tratamiento , Síndromes de Tricotiodistrofia/genética
3.
Mol Genet Metab ; 126(4): 475-488, 2019 04.
Artículo en Inglés | MEDLINE | ID: mdl-30691927

RESUMEN

GM3 synthase, encoded by ST3GAL5, initiates synthesis of all downstream cerebral gangliosides. Here, we present biochemical, functional, and natural history data from 50 individuals homozygous for a pathogenic ST3GAL5 c.862C>T founder allele (median age 8.1, range 0.7-30.5 years). GM3 and its derivatives were undetectable in plasma. Weight and head circumference were normal at birth and mean Apgar scores were 7.7 ±â€¯2.0 (1 min) and 8.9 ±â€¯0.5 (5 min). Somatic growth failure, progressive microcephaly, global developmental delay, visual inattentiveness, and dyskinetic movements developed within a few months of life. Infantile-onset epileptic encephalopathy was characterized by a slow, disorganized, high-voltage background, poor state transitions, absent posterior rhythm, and spike trains from multiple independent cortical foci; >90% of electrographic seizures were clinically silent. Hearing loss affected cochlea and central auditory pathways and 76% of children tested failed the newborn hearing screen. Development stagnated early in life; only 13 (26%) patients sat independently (median age 30 months), three (6%) learned to crawl, and none achieved reciprocal communication. Incessant irritability, often accompanied by insomnia, began during infancy and contributed to high parental stress. Despite catastrophic neurological dysfunction, neuroimaging showed only subtle or no destructive changes into late childhood and hospitalizations were surprisingly rare (0.2 per patient per year). Median survival was 23.5 years. Our observations corroborate findings from transgenic mice which indicate that gangliosides might have a limited role in embryonic neurodevelopment but become vital for postnatal brain growth and function. These results have critical implications for the design and implementation of ganglioside restitution therapies.


Asunto(s)
Epilepsia/tratamiento farmacológico , Epilepsia/genética , Gangliósidos/fisiología , Sialiltransferasas/deficiencia , Adolescente , Adulto , Alelos , Puntaje de Apgar , Niño , Preescolar , Epilepsia/complicaciones , Femenino , Glicoesfingolípidos/sangre , Homocigoto , Humanos , Lactante , Masculino , Microcefalia , Estudios Retrospectivos , Convulsiones , Sialiltransferasas/sangre , Sialiltransferasas/genética , Estados Unidos , Adulto Joven
4.
J Cell Biochem ; 115(7): 1243-53, 2014 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-24415158

RESUMEN

Osteoactivin (OA), also known as glycoprotein nmb (gpnmb) plays an important role in the regulation of osteoblast differentiation and function. OA induced osteoblast differentiation and function in vitro by stimulating alkaline phosphatase (ALP) activity, osteocalcin production, nodule formation, and matrix mineralization. Recent studies reported a role for OA in cell adhesion and integrin binding. In this study, we demonstrate that recombinant osteoactivin (rOA) as a matricellular protein stimulated adhesion, spreading and differentiation of MC3T3-E1 osteoblast-like cells through binding to αv ß1 integrin and heparan sulfated proteoglycans (HSPGs). MC3T3-E1 cell adhesion to rOA was blocked by neutralizing anti-OA or anti-αv and ß1 integrin antibodies. rOA stimulated-osteoblast adhesion was also inhibited by soluble heparin and sodium chlorate. Interestingly, rOA stimulated-osteoblast adhesion promoted an increase in FAK and ERK activation, resulting in the formation of focal adhesions, cell spreading and enhanced actin cytoskeleton organization. In addition, differentiation of primary osteoblasts was augmented on rOA coated-wells marked by increased alkaline phosphatase staining and activity. Taken together, these data implicate OA as a matricellular protein that stimulates osteoblast adhesion through binding to αv ß1 integrin and cell surface HSPGs, resulting in increased cell spreading, actin reorganization, and osteoblast differentiation with emphasis on the positive role of OA in osteogenesis.


Asunto(s)
Proteínas del Ojo/metabolismo , Proteoglicanos de Heparán Sulfato/metabolismo , Glicoproteínas de Membrana/metabolismo , Osteoblastos/fisiología , Receptores de Vitronectina/metabolismo , Células 3T3 , Citoesqueleto de Actina/fisiología , Fosfatasa Alcalina/biosíntesis , Animales , Anticuerpos/inmunología , Adhesión Celular , Diferenciación Celular , Línea Celular , Proliferación Celular , Cloratos/farmacología , Quinasas MAP Reguladas por Señal Extracelular/biosíntesis , Proteínas del Ojo/genética , Proteínas del Ojo/inmunología , Quinasa 1 de Adhesión Focal/biosíntesis , Adhesiones Focales , Heparina/farmacología , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/inmunología , Ratones , Ratones Endogámicos C57BL , Osteogénesis/fisiología , Unión Proteica , Ratas , Receptores de Vitronectina/inmunología , Proteínas Recombinantes
5.
JIMD Rep ; 63(5): 453-461, 2022 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-36101819

RESUMEN

Glycogen storage disease type 1a (GSD1a) is an inborn error of glucose metabolism characterized by fasting hypoglycemia, hepatomegaly, and growth failure. Late complications include nephropathy and hepatic adenomas. We conducted a retrospective observational study on a cohort of Amish patients with GSD1a. A total of 15 patients cared for at a single center, with a median age of 9.9 years (range 0.25-24 years) were included. All patients shared the same founder variant in GCPC c.1039 C > T. The phenotype of this cohort demonstrated good metabolic control with median cohort triglyceride level slightly above normal, no need for continuous overnight feeds, and a higher quality of life compared to a previous GSD cohort. The most frequent complications were oral aversion, gross motor delay, and renal hyperfiltration. We discuss our unique care delivery at a single center that cares for Amish patients with inherited disorders.

6.
Vaccine ; 39(7): 1058-1063, 2021 02 12.
Artículo en Inglés | MEDLINE | ID: mdl-33478791

RESUMEN

OBJECTIVES: The Holmes County Amish have low vaccination rates, an increasingly diverse population, and have an increased incidence of certain inherited diseases. The objectives were to evaluate; the rate and influences of vaccine hesitancy compared to a decade ago, vaccination patterns between Amish affiliations, vaccine practices of Amish special needs children, and the Amish's acceptance of a COVID-19 vaccine. STUDY DESIGN: In April of 2020, a survey assessing vaccination patterns and beliefs were mailed to 1000 Amish families, including ultra-conservative Amish sects and special needs families. RESULTS: The response rate was 39%. Among 391 respondents, 59% did not vaccinate their children, compared to only 14% that refused all vaccinations reported by Wenger et al in the same community only a decade ago. The ultra-conservative Amish rejected vaccines more often. Amish special needs children were more likely to receive vaccines than healthy Amish children. 75% responded they would reject a COVID-19 vaccine. Fear of adverse effects was the most common reason to reject vaccines. Families that accepted vaccines were more likely to cite a healthcare worker as the primary influence to vaccinate. Wives were more likely to cite their spouse as the primary influence to vaccinate. Families that rejected vaccines were more likely to state their bishop was the most influential person on vaccination. CONCLUSION: The Holmes County Amish have decreasing vaccine acceptance. Efforts to improve vaccination will require a targeted focus on the primary influences and beliefs of sub-populations within the Amish. Physician advocacy, peer mentorship, father-directed education, and close partnership with Church leadership will be needed to limit vaccine-preventable disease. The Amish may be at risk for low uptake of a COVID-19 vaccine.


Asunto(s)
Amish , COVID-19/prevención & control , Aceptación de la Atención de Salud/estadística & datos numéricos , Negativa a la Vacunación/estadística & datos numéricos , Vacunación/estadística & datos numéricos , Vacunas contra la COVID-19 , Niño , Conocimientos, Actitudes y Práctica en Salud , Humanos , Ohio , Vacunación/psicología
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