RESUMEN
Achondroplasia is a lifelong condition requiring lifelong management. There is consensus that infants and children with achondroplasia should be managed by a multidisciplinary team experienced in the condition. However, many people are lost to follow-up after the transition from paediatric to adult care, and there is no standardised approach for management in adults, despite the recent availability of international consensus guidelines. To address this, the European Achondroplasia Forum has developed a patient-held checklist to support adults with achondroplasia in managing their health. The checklist highlights key symptoms of spinal stenosis and obstructive sleep apnoea, both among the most frequent and potentially severe medical complications in adults with achondroplasia. The checklist acts as a framework to support individuals and their primary care provider in completing a routine review. General advice on issues such as blood pressure, pain, hearing, weight, adaptive aids, and psychosocial aspects are also included. The checklist provides key symptoms to be aware of, in addition to action points so that people can approach their primary care provider and be directed to the appropriate specialist, if needed. Additionally, the European Achondroplasia Forum offers some ideas on implementing the checklist during the transition from paediatric to adult care, thus ensuring the existing multidisciplinary team model in place during childhood can support in engaging individuals and empowering them to take responsibility for their own care as they move into adulthood.
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Acondroplasia , Adulto , Humanos , Acondroplasia/complicaciones , Acondroplasia/terapia , Lista de Verificación , Europa (Continente) , Apnea Obstructiva del Sueño/terapia , Estenosis Espinal/terapia , Estenosis Espinal/complicaciones , Transición a la Atención de AdultosRESUMEN
CONTEXT: Osteopathia striata with cranial sclerosis (OSCS) is a rare bone disorder with X-linked dominant inheritance, characterized by a generalized hyperostosis in the skull and long bones and typical metaphyseal striations in the long bones. So far, loss-of-function variants in AMER1 (also known as WTX or FAM123B), encoding the APC membrane recruitment protein 1 (AMER1), have been described as the only molecular cause for OSCS. AMER1 promotes the degradation of ß-catenin via AXIN stabilization, acting as a negative regulator of the WNT/ß-catenin signaling pathway, a central pathway in bone formation. OBJECTIVE: In this study, we describe a Dutch adult woman with an OSCS-like phenotype, namely, generalized high bone mass and characteristic metaphyseal striations, but no genetic variant affecting AMER1. RESULTS: Whole exome sequencing led to the identification of a mosaic missense variant (c.876A > C; p.Lys292Asn) in CTNNB1, coding for ß-catenin. The variant disrupts an amino acid known to be crucial for interaction with AXIN, a key factor in the ß-catenin destruction complex. Western blotting experiments demonstrate that the p.Lys292Asn variant does not significantly affect the ß-catenin phosphorylation status, and hence stability in the cytoplasm. Additionally, luciferase reporter assays were performed to investigate the effect of p.Lys292Asn ß-catenin on canonical WNT signaling. These studies indicate an average 70-fold increase in canonical WNT signaling activity by p.Lys292Asn ß-catenin. CONCLUSION: In conclusion, this study indicates that somatic variants in the CTNNB1 gene could explain the pathogenesis of unsolved cases of osteopathia striata.
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Mosaicismo , Osteosclerosis , beta Catenina , Humanos , beta Catenina/genética , beta Catenina/metabolismo , Femenino , Osteosclerosis/genética , Osteosclerosis/patología , Mutación Missense , Adulto , Vía de Señalización Wnt/genética , Persona de Mediana Edad , Secuenciación del Exoma , Proteínas Supresoras de Tumor , Proteínas Adaptadoras Transductoras de SeñalesRESUMEN
Pathogenic variants disrupting the binding between sclerostin (encoded by SOST) and its receptor LRP4 have previously been described to cause sclerosteosis, a rare high bone mass disorder. The sclerostin-LRP4 complex inhibits canonical WNT signaling, a key pathway regulating osteoblastic bone formation and a promising therapeutic target for common bone disorders, such as osteoporosis. In the current study, we crossed mice deficient for Sost (Sost-/-) with our p.Arg1170Gln Lrp4 knock-in (Lrp4KI/KI) mouse model to create double mutant Sost-/-;Lrp4KI/KI mice. We compared the phenotype of Sost-/- mice with that of Sost-/-;Lrp4KI/KI mice, to investigate a possible synergistic effect of the disease-causing p.Arg1170Trp variant in Lrp4 on Sost deficiency. Interestingly, presence of Lrp4KI alleles partially mitigated the Sost-/- phenotype. Cellular and dynamic histomorphometry did not reveal mechanistic insights into the observed phenotypic differences. We therefore determined the molecular effect of the Lrp4KI allele by performing bulk RNA sequencing on Lrp4KI/KI primary osteoblasts. Unexpectedly, mostly genes related to bone resorption or remodeling (Acp5, Rankl, Mmp9) were upregulated in Lrp4KI/KI primary osteoblasts. Verification of these markers in Lrp4KI/KI, Sost-/- and Sost-/-;Lrp4KI/KI mice revealed that sclerostin deficiency counteracts this Lrp4KI/KI effect in Sost-/-;Lrp4KI/KI mice. We therefore hypothesize that models with two inactivating Lrp4KI alleles rather activate bone remodeling, with a net gain in bone mass, whereas sclerostin deficiency has more robust anabolic effects on bone formation. Moreover, these effects of sclerostin and Lrp4 are stronger in female mice, contributing to a more severe phenotype than in males and more detectable phenotypic differences among different genotypes.
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Proteínas Adaptadoras Transductoras de Señales , Remodelación Ósea , Hiperostosis , Sindactilia , Masculino , Femenino , Animales , Ratones , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Ratones Noqueados , Fenotipo , Mutación , Remodelación Ósea/genética , Proteínas Relacionadas con Receptor de LDL/genética , Proteínas Relacionadas con Receptor de LDL/metabolismoRESUMEN
Metaphyseal dysplasia with maxillary hypoplasia with or without brachydactyly (MDMHB) is an ultra-rare skeletal dysplasia caused by heterozygous intragenic RUNX2 duplications, comprising either exons 3 to 5 or exons 3 to 6 of RUNX2. In this study, we describe a 14-year-old Belgian boy with metaphyseal dysplasia with maxillary hypoplasia but without brachydactyly. Clinical and radiographic examination revealed mild facial dysmorphism, dental anomalies, enlarged clavicles, genua valga and metaphyseal flaring and thin cortices with an osteoporotic skeletal appearance. Exome sequencing led to the identification of a de novo heterozygous tandem duplication within RUNX2, encompassing exons 3 to 7. This duplication is larger than the ones previously reported in MDMHB cases since it extends into the C-terminal activation domain of RUNX2. We review previously reported cases with MDMHB and highlight the resemblance of this disorder with Pyle disease, which may be explained by intersecting molecular pathways between RUNX2 and sFRP4. This study expands our knowledge on the genotypic and phenotypic characteristics of MDMHB and the role of RUNX2 in rare bone disorders.
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Braquidactilia , Displasia Cleidocraneal , Micrognatismo , Osteocondrodisplasias , Masculino , Humanos , Adolescente , Subunidad alfa 1 del Factor de Unión al Sitio Principal/genética , Osteocondrodisplasias/diagnóstico por imagen , Osteocondrodisplasias/genética , Proteínas Proto-OncogénicasRESUMEN
Paget's disease of bone (PDB) is a common, late-onset bone disorder, characterized by focal increases of bone turnover that can result in bone lesions. Heterozygous pathogenic variants in the Sequestosome 1 (SQSTM1) gene are found to be the main genetic cause of PDB. More recently, PFN1 and ZNF687 have been identified as causal genes in patients with a severe, early-onset, polyostotic form of PDB, and an increased likelihood to develop giant cell tumors. In our study, we screened the coding regions of PFN1 and ZNF687 in a Belgian PDB cohort (n = 188). In the PFN1 gene, no variants could be identified, supporting the observation that variants in this gene are extremely rare in PDB. However, we identified 3 non-synonymous coding variants in ZNF687. Interestingly, two of these rare variants (p.Pro937His and p.Arg939Cys) were clustering in the nuclear localization signal of the encoded ZNF687 protein, also harboring the p.Pro937Arg variant, a previously reported disease-causing variant. In conclusion, our findings support the involvement of genetic variation in ZNF687 in the pathogenesis of classical PDB, thereby expanding its mutational spectrum.
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Osteítis Deformante , Humanos , Osteítis Deformante/genética , Osteítis Deformante/patología , Señales de Localización Nuclear/genética , Proteína Sequestosoma-1/genética , Pruebas Genéticas , Factores de Transcripción/genética , Mutación , Profilinas/genéticaRESUMEN
Foramen magnum stenosis is a serious, and potentially life-threatening complication of achondroplasia. The foramen magnum is smaller in infants with achondroplasia, compared with the general population, and both restricted growth in the first 2 years and premature closure of skull plate synchondroses can contribute to narrowing. Narrowing of the foramen magnum can lead to compression of the brainstem and spinal cord, and result in sleep apnoea and sudden death. There is a lack of clarity in the literature on the timing of regular monitoring for foramen magnum stenosis, which assessments should be carried out and when regular screening should be ceased. The European Achondroplasia Forum (EAF) is a group of clinicians and patient advocates, representative of the achondroplasia community. Members of the EAF Steering Committee were invited to submit suggestions for guiding principles for the detection and management of foramen magnum stenosis, which were collated and discussed at an open workshop. Each principle was scrutinised for content and wording, and anonymous voting held to pass the principle and vote on the level of agreement. A total of six guiding principles were developed which incorporate routine clinical monitoring of infants and young children, timing of routine MRI screening, referral of suspected foramen magnum stenosis to a neurosurgeon, the combination of assessments to inform the decision to decompress the foramen magnum, joint decision making to proceed with decompression, and management of older children in whom previously undetected foramen magnum stenosis is identified. All principles achieved the ≥ 75% majority needed to pass (range 89-100%), with high levels of agreement (range 7.6-8.9). By developing guiding principles for the detection and management of foramen magnum stenosis, the EAF aim to enable infants and young children to receive optimal monitoring for this potentially life-threatening complication.
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Acondroplasia , Enfermedades Óseas , Síndromes de la Apnea del Sueño , Niño , Lactante , Humanos , Adolescente , Preescolar , Foramen Magno/cirugía , Constricción Patológica/diagnóstico , Constricción Patológica/complicaciones , Acondroplasia/diagnóstico , Acondroplasia/terapia , Acondroplasia/complicaciones , Síndromes de la Apnea del Sueño/diagnóstico , Médula Espinal , Enfermedades Óseas/complicacionesRESUMEN
Introduction: Spondylocostal dysostosis (SCD) is characterized by multiple vertebral abnormalities associated with abnormalities of the ribs. Five genes causative for the disease have been identified. These include DLL3 (OMIM *602768), MESP2 (OMIM #608681), LFNG (OMIM #609813), TBX6 (OMIM *602427), and HES7 (OMIM *608059). Methods: In the current study, we investigated a Pakistani consanguineous family segregating spondylocostal dysotosis. Whole-exome sequencing (WES) followed by Sanger sequencing was performed using DNA of affected and unaffected individuals to identify pathogenic variant(s). The identified variant was interpreted using ACMG classification. Literature review was performed to summarize currently known mutated alleles of DLL3 and the underlying clinical phenotypes. Results: Clinical examination using anthropometric measurements and radiographs diagnosed the patients to be afflicted with SCD. Pedigree analysis of the affected family showed an autosomal recessive inheritance pattern of the disease. WES followed by Sanger sequencing identified a novel homozygous nonsense variant (DLL3(NM_016941.4): c.535G>T; p.Glu179Ter) in the DLL3 gene located on chromosome 19q13.2. Conclusion: The study will be helpful in carrier testing and genetic counseling to prevent segregation of the disease to the next generations within this family. It also provides knowledge for clinicians and researchers in search of a better understanding of SCD anomalies.
RESUMEN
Spondyloepiphyseal dysplasia congenita (SEDC) is a severe non-lethal type 2 collagenopathy caused by pathogenic variants in the COL2A1 gene, which encodes the alpha-1 chain of type II collagen. SEDC is clinically characterized by severe short stature, degenerative joint disease, hearing impairment, orofacial anomalies and ocular manifestations. To study and therapeutically target the underlying disease mechanisms, human iPSC-chondrocytes are considered highly suitable as they have been shown to exhibit several key features of skeletal dysplasias. Prior to creating iPSC-chondrocytes, peripheral blood mononuclear cells of two male SEDC patients, carrying the p.Gly1107Arg and p.Gly408Asp pathogenic variants, respectively, were successfully reprogrammed into iPSCs using the CytoTune™-iPS 2.0 Sendai Kit (Invitrogen).
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Células Madre Pluripotentes Inducidas , Osteocondrodisplasias , Humanos , Masculino , Leucocitos Mononucleares , Osteocondrodisplasias/genética , Colágeno Tipo II/genéticaRESUMEN
The "Nosology of genetic skeletal disorders" has undergone its 11th revision and now contains 771 entries associated with 552 genes reflecting advances in molecular delineation of new disorders thanks to advances in DNA sequencing technology. The most significant change as compared to previous versions is the adoption of the dyadic naming system, systematically associating a phenotypic entity with the gene it arises from. We consider this a significant step forward as dyadic naming is more informative and less prone to errors than the traditional use of list numberings and eponyms. Despite the adoption of dyadic naming, efforts have been made to maintain strong ties to the MIM catalog and its historical data. As with the previous versions, the list of disorders and genes in the Nosology may be useful in considering the differential diagnosis in the clinic, directing bioinformatic analysis of next-generation sequencing results, and providing a basis for novel advances in biology and medicine.
RESUMEN
Hemizygous missense variants in the X-linked BGN gene, encoding the extracellular matrix protein biglycan, cause spondyloepimetaphyseal dysplasia (SEMD, biglycan type), which is clinically characterized by short stature, brachydactyly and osteoarthritis. Little is known about the pathomechanisms underlying SEMD, biglycan type. IPSC-derived chondrocyte disease models have been shown to exhibit several key aspects of known disease mechanisms of skeletal dysplasias and are therefore considered highly suitable human disease models to study SEMD, biglycan type. Prior to creating iPSC-chondrocytes, dermal fibroblasts of two male patients with SEMD, biglycan type, carrying the p.Gly259Val variant were successfully reprogrammed into iPSCs using the CytoTuneTM-iPS 2.0 Sendai Kit (Invitrogen).
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Células Madre Pluripotentes Inducidas , Osteocondrodisplasias , Humanos , Masculino , Biglicano/genética , Osteocondrodisplasias/genética , Mutación Missense , Proteínas de la Matriz Extracelular/genéticaRESUMEN
BACKGROUND: Cleidocranial dysplasia (CCD) is a rare skeletal dysplasia with significant clinical variability. Patients with CCD typically present with delayed closure of fontanels and cranial sutures, dental anomalies, clavicular hypoplasia or aplasia and short stature. Runt-related transcription factor 2 (RUNX2) is currently the only known disease-causing gene for CCD, but several studies have suggested locus heterogeneity. METHODS: The cohort consists of eight subjects from five unrelated families partially identified through GeneMatcher. Exome or genome sequencing was applied and in two subjects the effect of the variant was investigated at RNA level. RESULTS: In each subject a heterozygous pathogenic variant in CBFB was detected, whereas no genomic alteration involving RUNX2 was found. Three CBFB variants (one splice site alteration, one nonsense variant, one 2 bp duplication) were shown to result in a premature stop codon. A large intragenic deletion was found to delete exon 4, without affecting CBFB expression. The effect of a second splice site variant could not be determined but most likely results in a shortened or absent protein. Affected individuals showed similarities with RUNX2-related CCD, including dental and clavicular abnormalities. Normal stature and neurocognitive problems were however distinguishing features. CBFB encodes the core-binding factor ß subunit, which can interact with all RUNX proteins (RUNX1, RUNX2, RUNX3) to form heterodimeric transcription factors. This may explain the phenotypic differences between CBFB-related and RUNX2-related CCD. CONCLUSION: We confirm the previously suggested locus heterogeneity for CCD by identifying five pathogenic variants in CBFB in a cohort of eight individuals with clinical and radiographic features reminiscent of CCD.
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Displasia Cleidocraneal , Subunidad beta del Factor de Unión al Sitio Principal , Humanos , Secuencia de Bases , Displasia Cleidocraneal/genética , Displasia Cleidocraneal/patología , Codón sin Sentido , Subunidad alfa 1 del Factor de Unión al Sitio Principal/genética , Subunidad beta del Factor de Unión al Sitio Principal/genética , ExonesRESUMEN
Varicella-zoster virus (VZV) infection of neuronal cells and the activation of cell-intrinsic antiviral responses upon infection are still poorly understood mainly due to the scarcity of suitable human in vitro models that are available to study VZV. We developed a compartmentalized human-induced pluripotent stem cell (hiPSC)-derived neuronal culture model that allows axonal VZV infection of the neurons, thereby mimicking the natural route of infection. Using this model, we showed that hiPSC-neurons do not mount an effective interferon-mediated antiviral response following VZV infection. Indeed, in contrast to infection with Sendai virus, VZV infection of the hiPSC-neurons does not result in the upregulation of interferon-stimulated genes (ISGs) that have direct antiviral functions. Furthermore, the hiPSC-neurons do not produce interferon-α (IFNα), a major cytokine that is involved in the innate antiviral response, even upon its stimulation with strong synthetic inducers. In contrast, we showed that exogenous IFNα effectively limits VZV spread in the neuronal cell body compartment and demonstrated that ISGs are efficiently upregulated in these VZV-infected neuronal cultures that are treated with IFNα. Thus, whereas the cultured hiPSC neurons seem to be poor IFNα producers, they are good IFNα responders. This could suggest an important role for other cells such as satellite glial cells or macrophages to produce IFNα for VZV infection control.
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Varicela , Herpes Zóster , Células Madre Pluripotentes Inducidas , Interferón-alfa , Neuronas , Humanos , Herpesvirus Humano 3/fisiología , Células Madre Pluripotentes Inducidas/virología , Interferón-alfa/inmunología , Neuronas/virología , Células CultivadasRESUMEN
BACKGROUND: Achondroplasia is a genetic condition that can cause complications across the lifespan. While complications in childhood are well documented, the natural history of achondroplasia in adults has, until recently, been relatively lacking, and little is known about the care they receive or how they access it. The European Achondroplasia Forum undertook two exploratory surveys, one for healthcare professionals (HCPs) and one for patient advocacy group (PAG) representatives, to gain an understanding of current practices of the transition process of individuals with achondroplasia from paediatric to adult services and how adults perceive their care. RESULTS: Most HCP respondents followed up more children than adults, and 8/15 responded that individuals did not transition to an adult multidisciplinary team (MDT) after paediatric care. Of 10 PAG respondents, none considered the experience of transition to adult services as good or very good and 50% considered it to be poor or very poor. A total of 64% (7/11) described the coordination of transition to adult services as "Not satisfactory" or "Poor". HCPs and PAG representatives largely agreed on the core specialists involved in adult care (orthopaedic surgeons, physiotherapists, rehabilitation specialists, rheumatologists, clinical geneticists). However, there was a discrepancy in the understanding of healthcare needs outside of this, with PAG representatives selecting neurosurgeons and genetic counsellors, while HCPs selected pulmonologists and obstetricians/gynaecologists. There was agreement between HCP and PAG respondents on the key barriers to effective care of adults with achondroplasia, with lack of an adult MDT, lack of interest from individuals in accessing care, and less experience in adult than paediatric MDTs ranking highly. CONCLUSIONS: This study indicates that the care and follow up of adults with achondroplasia is challenging. Individuals are often lost to, or decline, follow up as they leave paediatric care, and it is largely unknown how, where, and why adults with achondroplasia access care later in life. Lifelong, multidisciplinary specialist care led by an identified physician should be accessible to all individuals with achondroplasia. It is important to ensure barriers to optimal care are addressed to enable access to appropriate care for all individuals with achondroplasia.
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Acondroplasia , Acondroplasia/terapia , Adulto , Niño , Atención a la Salud , Estudios de Seguimiento , Humanos , Encuestas y CuestionariosRESUMEN
BACKGROUND: Achondroplasia is the most common form of skeletal dysplasia, with serious comorbidities and complications that may occur from early infancy to adulthood, requiring lifelong management from a multidisciplinary team expert in the condition The European Achondroplasia Forum guiding principles of management highlight the importance of accurate diagnosis and timely referral to a centre specialised in the management of achondroplasia to fully support individuals with achondroplasia and their families, and to appropriately plan management. The European Achondroplasia Forum undertook an exploratory audit of its Steering Committee to ascertain the current situation in Europe and to understand the potential barriers to timely diagnosis and referral. RESULTS: Diagnosis of achondroplasia was primarily confirmed prenatally (66.6%), at Day 0 (12.8%) or within one month after birth (12.8%). For suspected and confirmed cases of achondroplasia, a greater proportion were identified earlier in the prenatal period (87.1%) with fewer diagnoses at Day 0 (5.1%) or within the first month of life (2.6%). Referral to a specialist centre took place after birth (86.6%), predominantly within the first month, although there was a wide variety in the timepoint of referral between countries and in the time lapsed between suspicion or confirmed diagnosis of achondroplasia and referral to a specialist centre. CONCLUSIONS: The European Achondroplasia Forum guiding principles of management recommend diagnosis of achondroplasia as early as possible. If concerns are raised at routine ultrasound, second line investigation should be implemented so that the diagnosis can be reached as soon as possible for ongoing management. Clinical and radiological examination supported by molecular testing is the most effective way to confirm diagnosis of achondroplasia after birth. Referral to a centre specialised in achondroplasia care should be made as soon as possible on suspicion or confirmation of diagnosis. In countries or regions where there are no official skeletal dysplasia reference or specialist centres, priority should be given to their creation or recognition, together with incentives to improve the structure of the existing multidisciplinary team managing achondroplasia. The length of delay between diagnosis of achondroplasia and referral to a specialist centre warrants further research.
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Acondroplasia , Acondroplasia/complicaciones , Acondroplasia/diagnóstico , Adulto , Europa (Continente) , Femenino , Humanos , Embarazo , Diagnóstico Prenatal , Derivación y Consulta , UltrasonografíaRESUMEN
Steel syndrome (MIM# 615155) is an autosomal recessive skeletal disorder, characterized by dislocations of the hips and radial heads, carpal coalition, short stature, facial dysmorphism, and scoliosis. Until date 47 patients have been reported. However, disease causing variants have been identified only in twenty Puerto Rican and nine non-Puerto Rican families. Here we report two monozygotic twins and a boy from two families with novel missense variants, c.295G > A p.(Ala99 Thr), c.3056C > A p.(Pro1019His) and c.2521G > A p.(Gly841Arg) in COL27A1. We describe for the first time, cleft palate and delayed carpal bone ossification as features of Steel syndrome. We reviewed clinical features in all mutation-proven Steel syndrome patients. Short stature and dislocation/subluxation of hip joint are consistently observed. Other features include dislocated radial heads, scoliosis, lordosis, carpal coalition, facial dysmorphism, hearing loss, bilateral fifth finger clinodactyly, knee deformities and developmental delay. Seven missense variants and eight null variants are reported in COL27A1 until date. We also looked into the genotype-phenotype correlation in Puerto Rican and non-Puerto Rican patients.
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Luxaciones Articulares , Escoliosis , Colágenos Fibrilares/genética , Humanos , Mutación , Fenotipo , Escoliosis/diagnóstico por imagen , Escoliosis/genética , Gemelos Monocigóticos/genéticaRESUMEN
BNIP1 (BCL2 interacting protein 1) is a soluble N-ethylmaleimide-sensitive factor-attachment protein receptor involved in ER membrane fusion. We identified the homozygous BNIP1 intronic variant c.84+3A>T in the apparently unrelated patients 1 and 2 with disproportionate short stature. Radiographs showed abnormalities affecting both the axial and appendicular skeleton and spondylo-epiphyseal dysplasia. We detected ~80% aberrantly spliced BNIP1 pre-mRNAs, reduced BNIP1 mRNA level to ~80%, and BNIP1 protein level reduction by ~50% in patient 1 compared to control fibroblasts. The BNIP1 ortholog in Drosophila, Sec20, regulates autophagy and lysosomal degradation. We assessed lysosome positioning and identified a decrease in lysosomes in the perinuclear region and an increase in the cell periphery in patient 1 cells. Immunofluorescence microscopy and immunoblotting demonstrated an increase in LC3B-positive structures and LC3B-II levels, respectively, in patient 1 fibroblasts under steady-state condition. Treatment of serum-starved fibroblasts with or without bafilomycin A1 identified significantly decreased autophagic flux in patient 1 cells. Our data suggest a block at the terminal stage of autolysosome formation and/or clearance in patient fibroblasts. BNIP1 together with RAB33B and VPS16, disease genes for Smith-McCort dysplasia 2 and a multisystem disorder with short stature, respectively, highlight the importance of autophagy in skeletal development.
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Autofagosomas , Autofagia , Animales , Autofagosomas/metabolismo , Autofagia/genética , Drosophila , Homocigoto , Humanos , Lisosomas/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-2/metabolismoRESUMEN
CONTEXT: Natriuretic peptide receptor-C (NPR-C, encoded by NPR3) belongs to a family of cell membrane-integral proteins implicated in various physiological processes, including longitudinal bone growth. NPR-C acts as a clearance receptor of natriuretic peptides, including C-type natriuretic peptide (CNP), that stimulate the cGMP-forming guanylyl cyclase-coupled receptors NPR-A and NPR-B. Pathogenic variants in CNP, NPR2, and NPR3 may cause a tall stature phenotype associated with macrodactyly of the halluces and epiphyseal dysplasia. OBJECTIVE: Here we report on a boy with 2 novel biallelic inactivating variants of NPR3. METHODS: History and clinical characteristics were collected. Biochemical indices of natriuretic peptide clearance and in vitro cellular localization of NPR-C were studied to investigate causality of the identified variants. RESULTS: We identified 2 novel compound heterozygous NPR3 variants c.943G>A p.(Ala315Thr) and c.1294A>T p.(Ile432Phe) in a boy with tall stature and macrodactyly of the halluces. In silico analysis indicated decreased stability of NPR-C, presumably resulting in increased degradation or trafficking defects. Compared to other patients with NPR-C loss-of-function, the phenotype seemed to be milder: pseudo-epiphyses in hands and feet were absent, biochemical features were less severe, and there was some co-localization of p.(Ile432Phe) NPR-C with the cell membrane, as opposed to complete cytoplasmic retention. CONCLUSION: With this report on a boy with tall stature and macrodactyly of the halluces we further broaden the genotypic and phenotypic spectrum of NPR-C-related tall stature.
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Induced pluripotent stem cell (iPSC) technology allows pathomechanistic and therapeutic investigation of human heritable disorders affecting tissue types whose collection from patients is difficult or even impossible. Among them are cartilage diseases. Over the past decade, iPSC-chondrocyte disease models have been shown to exhibit several key aspects of known disease mechanisms. Concurrently, an increasing number of protocols to differentiate iPSCs into chondrocytes have been published, each with its respective (dis)advantages. In this review we provide a comprehensive overview of the different differentiation approaches, the hitherto described iPSC-chondrocyte disease models and mechanistic and/or therapeutic insights that have been derived from their investigation, and the current model limitations. Key lessons are that the most appropriate differentiation approach is dependent upon the cartilage disease under investigation and that further optimization is still required to recapitulate the in vivo cartilage. © 2022 American Society for Bone and Mineral Research (ASBMR).
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Enfermedades de los Cartílagos , Células Madre Pluripotentes Inducidas , Cartílago/metabolismo , Enfermedades de los Cartílagos/metabolismo , Diferenciación Celular , Condrocitos/metabolismo , Descubrimiento de Drogas , HumanosRESUMEN
Antigen recognition through the T cell receptor (TCR) αß heterodimer is one of the primary determinants of the adaptive immune response. Vaccines activate naïve T cells with high specificity to expand and differentiate into memory T cells. However, antigen-specific memory CD4 T cells exist in unexposed antigen-naïve hosts. In this study, we use high-throughput sequencing of memory CD4 TCRß repertoire and machine learning to show that individuals with preexisting vaccine-reactive memory CD4 T cell clonotypes elicited earlier and higher antibody titers and mounted a more robust CD4 T cell response to hepatitis B vaccine. In addition, integration of TCRß sequence patterns into a hepatitis B epitope-specific annotation model can predict which individuals will have an early and more vigorous vaccine-elicited immunity. Thus, the presence of preexisting memory T cell clonotypes has a significant impact on immunity and can be used to predict immune responses to vaccination.
Immune cells called CD4 T cells help the body build immunity to infections caused by bacteria and viruses, or after vaccination. Receptor proteins on the outside of the cells recognize pathogens, foreign molecules called antigens, or vaccine antigens. Vaccine antigens are usually inactivated bacteria or viruses, or fragments of these pathogens. After recognizing an antigen, CD4 T cells develop into memory CD4 T cells ready to defend against future infections with the pathogen. People who have never been exposed to a pathogen, or have never been vaccinated against it, may nevertheless have preexisting memory cells ready to defend against it. This happens because CD4 T cells can recognize multiple targets, which enables the immune system to be ready to defend against both new and familiar pathogens. Elias, Meysman, Bartholomeus et al. wanted to find out whether having preexisting memory CD4 T cells confers an advantage for vaccine-induced immunity. Thirty-four people who were never exposed to hepatitis B or vaccinated against it participated in the study. These individuals provided blood samples before vaccination, with 2 doses of the hepatitis B vaccine, and at 3 time points afterward. Using next generation immune sequencing and machine learning techniques, Elias et al. analyzed the individuals' memory CD4 T cells before and after vaccination. The experiments showed that preexisting memory CD4 T cells may determine vaccination outcomes, and people with more preexisting memory cells develop quicker and stronger immunity after vaccination against hepatitis B. This information may help scientists to better understand how people develop immunity to pathogens. It may guide them develop better vaccines or predict who will develop immunity after vaccination.