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1.
J Med Genet ; 61(6): 549-552, 2024 May 21.
Artículo en Inglés | MEDLINE | ID: mdl-38272662

RESUMEN

Fetal hydrops as detected by prenatal ultrasound usually carries a poor prognosis depending on the underlying aetiology. We describe the prenatal and postnatal clinical course of two unrelated female probands in whom de novo heterozygous missense variants in the planar cell polarity gene CELSR1 were detected using exome sequencing. Using several in vitro assays, we show that the CELSR1 p.(Cys1318Tyr) variant disrupted the subcellular localisation, affected cell-cell junction, impaired planar cell polarity signalling and lowered proliferation rate. These observations suggest that deleterious rare CELSR1 variants could be a possible cause of fetal hydrops.


Asunto(s)
Heterocigoto , Hidropesía Fetal , Mutación Missense , Humanos , Femenino , Mutación Missense/genética , Hidropesía Fetal/genética , Hidropesía Fetal/patología , Embarazo , Derrame Pleural/genética , Derrame Pleural/patología , Cadherinas/genética , Secuenciación del Exoma , Polaridad Celular/genética
2.
J Neurochem ; 157(4): 1331-1350, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-33090494

RESUMEN

Mutations in the X-linked gene coding for the calcium-/calmodulin-dependent serine protein kinase (CASK) are associated with severe neurological disorders ranging from intellectual disability (in males) to mental retardation and microcephaly with pontine and cerebellar hypoplasia. CASK is involved in transcription control, in the regulation of trafficking of the post-synaptic NMDA and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors, and acts as a presynaptic scaffolding protein. For CASK missense mutations, it is mostly unclear which of CASK's molecular interactions and cellular functions are altered and contribute to patient phenotypes. We identified five CASK missense mutations in male patients affected by neurodevelopmental disorders. These and five previously reported mutations were systematically analysed with respect to interaction with CASK interaction partners by co-expression and co-immunoprecipitation. We show that one mutation in the L27 domain interferes with binding to synapse-associated protein of 97 kDa. Two mutations in the guanylate kinase (GK) domain affect binding of CASK to the nuclear factors CASK-interacting nucleosome assembly protein (CINAP) and T-box, brain, 1 (Tbr1). A total of five mutations in GK as well as PSD-95/discs large/ZO-1 (PDZ) domains affect binding of CASK to the pre-synaptic cell adhesion molecule Neurexin. Upon expression in neurons, we observe that binding to Neurexin is not required for pre-synaptic localization of CASK. We show by bimolecular fluorescence complementation assay that Neurexin induces oligomerization of CASK, and that mutations in GK and PDZ domains interfere with the Neurexin-induced oligomerization of CASK. Our data are supported by molecular modelling, where we observe that the cooperative activity of PDZ, SH3 and GK domains is required for Neurexin binding and oligomerization of CASK.


Asunto(s)
Guanilato-Quinasas/genética , Moléculas de Adhesión de Célula Nerviosa/metabolismo , Trastornos del Neurodesarrollo/metabolismo , Animales , Humanos , Masculino , Modelos Moleculares , Mutación Missense , Unión Proteica , Ratas
3.
Brain ; 141(8): 2299-2311, 2018 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-29985992

RESUMEN

The transcription factor BCL11B is essential for development of the nervous and the immune system, and Bcl11b deficiency results in structural brain defects, reduced learning capacity, and impaired immune cell development in mice. However, the precise role of BCL11B in humans is largely unexplored, except for a single patient with a BCL11B missense mutation, affected by multisystem anomalies and profound immune deficiency. Using massively parallel sequencing we identified 13 patients bearing heterozygous germline alterations in BCL11B. Notably, all of them are affected by global developmental delay with speech impairment and intellectual disability; however, none displayed overt clinical signs of immune deficiency. Six frameshift mutations, two nonsense mutations, one missense mutation, and two chromosomal rearrangements resulting in diminished BCL11B expression, arose de novo. A further frameshift mutation was transmitted from a similarly affected mother. Interestingly, the most severely affected patient harbours a missense mutation within a zinc-finger domain of BCL11B, probably affecting the DNA-binding structural interface, similar to the recently published patient. Furthermore, the most C-terminally located premature termination codon mutation fails to rescue the progenitor cell proliferation defect in hippocampal slice cultures from Bcl11b-deficient mice. Concerning the role of BCL11B in the immune system, extensive immune phenotyping of our patients revealed alterations in the T cell compartment and lack of peripheral type 2 innate lymphoid cells (ILC2s), consistent with the findings described in Bcl11b-deficient mice. Unsupervised analysis of 102 T lymphocyte subpopulations showed that the patients clearly cluster apart from healthy children, further supporting the common aetiology of the disorder. Taken together, we show here that mutations leading either to BCL11B haploinsufficiency or to a truncated BCL11B protein clinically cause a non-syndromic neurodevelopmental delay. In addition, we suggest that missense mutations affecting specific sites within zinc-finger domains might result in distinct and more severe clinical outcomes.


Asunto(s)
Trastornos del Neurodesarrollo/genética , Proteínas Represoras/genética , Proteínas Represoras/fisiología , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/fisiología , Adolescente , Animales , Niño , Preescolar , Femenino , Regulación de la Expresión Génica/genética , Mutación de Línea Germinal , Haploinsuficiencia , Heterocigoto , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Lactante , Linfocitos/patología , Linfocitos/fisiología , Masculino , Ratones , Mutación , Proteínas Represoras/metabolismo , Linfocitos T/fisiología , Factores de Transcripción/genética , Proteínas Supresoras de Tumor/metabolismo
4.
Am J Med Genet A ; 176(3): 663-667, 2018 03.
Artículo en Inglés | MEDLINE | ID: mdl-29314551

RESUMEN

Sheldon-Hall syndrome (SHS) is the most common of the distal arthrogryposes (DAs), a group of disorders characterized by congenital non-progressive contractures. Patients with SHS present with contractures of the limbs and a distinctive triangular facies with prominent nasolabial folds. Calcaneovalgus deformity is frequent, as well as camptodactyly and ulnar deviation. Causative mutations in at least four different genes have been reported (MYH3, TNNI2, TPM2, and TNNT3). MYH3 plays a pivotal role in fetal muscle development and mutations in this gene are associated with Freeman-Sheldon syndrome, distal arthrogryposis 8 (DA8), and autosomal dominant spondylocarpotarsal synostosis. The last two disorders are characterized by skeletal abnormalities, in particular bony fusions. The observation that MYH3 may be mutated in these syndromes has suggested the involvement of this gene in bone development. We report the case of a boy with a novel pathogenic MYH3 mutation, presenting with the classical clinical features of SHS in association with unilateral carpal bone fusion and multiple vertebral fusions. This distinctive phenotype has never been reported in the literature so far and expands the phenotypic spectrum of SHS, endorsing the clinical variability of patients with MYH3-related disorders. Our findings also support a role for MYH3 in both muscle and bone development, suggesting a phenotypic continuum in MYH3-related disorders.


Asunto(s)
Artrogriposis/diagnóstico , Artrogriposis/genética , Proteínas del Citoesqueleto/genética , Mutación , Fenotipo , Columna Vertebral/anomalías , Niño , Hibridación Genómica Comparativa , Facies , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Humanos , Masculino , Radiografía
5.
Life (Basel) ; 14(5)2024 May 14.
Artículo en Inglés | MEDLINE | ID: mdl-38792648

RESUMEN

Fryns syndrome (FS) is a multiple congenital anomaly syndrome with different multisystemic malformations. These include congenital diaphragmatic hernia, pulmonary hypoplasia, and craniofacial dysmorphic features in combination with malformations of the central nervous system such as agenesis of the corpus callosum, cerebellar hypoplasia, and enlarged ventricles. We present a non-consanguineous northern European family with two recurrent cases of FS: a boy with multiple congenital malformations who died at the age of 2.5 months and a female fetus with a complex developmental disorder with similar features in a following pregnancy. Quad whole exome analysis revealed two likely splicing-affecting disease-causing mutations in the PIGN gene: a synonymous mutation c.2619G>A, p.(Leu873=) in the last nucleotide of exon 29 and a 30 bp-deletion c.996_1023+2del (NM_176787.5) protruding into intron 12, with both mutations in trans configuration in the affected patients. Exon skipping resulting from these two variants was confirmed via RNA sequencing. Our molecular and clinical findings identified compound heterozygosity for two novel splice-affecting variants as the underlying pathomechanism for the development of FS in two patients.

6.
Cell Rep Med ; 5(7): 101647, 2024 Jul 16.
Artículo en Inglés | MEDLINE | ID: mdl-39019006

RESUMEN

Congenital hydrocephalus (CH), occurring in approximately 1/1,000 live births, represents an important clinical challenge due to the limited knowledge of underlying molecular mechanisms. The discovery of novel CH genes is thus essential to shed light on the intricate processes responsible for ventricular dilatation in CH. Here, we identify FLVCR1 (feline leukemia virus subgroup C receptor 1) as a gene responsible for a severe form of CH in humans and mice. Mechanistically, our data reveal that the full-length isoform encoded by the FLVCR1 gene, FLVCR1a, interacts with the IP3R3-VDAC complex located on mitochondria-associated membranes (MAMs) that controls mitochondrial calcium handling. Loss of Flvcr1a in mouse neural progenitor cells (NPCs) affects mitochondrial calcium levels and energy metabolism, leading to defective cortical neurogenesis and brain ventricle enlargement. These data point to defective NPCs calcium handling and metabolic activity as one of the pathogenetic mechanisms driving CH.


Asunto(s)
Calcio , Hidrocefalia , Proteínas de Transporte de Membrana , Mitocondrias , Células-Madre Neurales , Receptores Virales , Animales , Humanos , Ratones , Calcio/metabolismo , Hidrocefalia/metabolismo , Hidrocefalia/genética , Hidrocefalia/patología , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Receptores de Inositol 1,4,5-Trifosfato/genética , Proteínas de Transporte de Membrana/metabolismo , Proteínas de Transporte de Membrana/genética , Mitocondrias/metabolismo , Células-Madre Neurales/metabolismo , Células-Madre Neurales/patología , Neurogénesis/genética , Receptores Virales/metabolismo , Receptores Virales/genética
7.
medRxiv ; 2024 May 05.
Artículo en Inglés | MEDLINE | ID: mdl-38746364

RESUMEN

Retinoblastoma (RB) proteins are highly conserved transcriptional regulators that play important roles during development by regulating cell-cycle gene expression. RBL2 dysfunction has been linked to a severe neurodevelopmental disorder. However, to date, clinical features have only been described in six individuals carrying five biallelic predicted loss of function (pLOF) variants. To define the phenotypic effects of RBL2 mutations in detail, we identified and clinically characterized a cohort of 28 patients from 18 families carrying LOF variants in RBL2 , including fourteen new variants that substantially broaden the molecular spectrum. The clinical presentation of affected individuals is characterized by a range of neurological and developmental abnormalities. Global developmental delay and intellectual disability were uniformly observed, ranging from moderate to profound and involving lack of acquisition of key motor and speech milestones in most patients. Frequent features included postnatal microcephaly, infantile hypotonia, aggressive behaviour, stereotypic movements and non-specific dysmorphic features. Common neuroimaging features were cerebral atrophy, white matter volume loss, corpus callosum hypoplasia and cerebellar atrophy. In parallel, we used the fruit fly, Drosophila melanogaster , to investigate how disruption of the conserved RBL2 orthologueue Rbf impacts nervous system function and development. We found that Drosophila Rbf LOF mutants recapitulate several features of patients harboring RBL2 variants, including alterations in the head and brain morphology reminiscent of microcephaly, and perturbed locomotor behaviour. Surprisingly, in addition to its known role in controlling tissue growth during development, we find that continued Rbf expression is also required in fully differentiated post-mitotic neurons for normal locomotion in Drosophila , and that adult-stage neuronal re-expression of Rbf is sufficient to rescue Rbf mutant locomotor defects. Taken together, this study provides a clinical and experimental basis to understand genotype-phenotype correlations in an RBL2 -linked neurodevelopmental disorder and suggests that restoring RBL2 expression through gene therapy approaches may ameliorate aspects of RBL2 LOF patient symptoms.

8.
Am J Med Genet A ; 161A(10): 2634-40, 2013 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-23949945

RESUMEN

An increasing number of patients with 3p proximal deletions were reported in the previous decade, but the region responsible for the main features such as intellectual disability (ID) and developmental delay is not yet characterized. Here we report on two monozygotic twin brothers of 2 10/12 years and an 18-year-old man, all three of them displaying severe ID, psychomotoric delay, autistic features, and only mild facial dysmorphisms. Array CGH (aCGH), revealed a 6.55 Mb de novo interstitial deletion of 3p14.1p14.3 in the twin brothers and a 4.76 Mb interstitial deletion of 3p14.1p14.2 in the 18-year-old patient, respectively. We compared the malformation spectrum with previous molecularly well-defined patients in the literature and in the DECIPHER database (Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources; http://decipher.sanger.ac.uk/). In conclusion, the deletion of a region containing 3p14.2 seems to be associated with a relative concise phenotype including ID and developmental delay. Thus, we hypothesize that 3p14.2 is the potential core region in 3p proximal deletions. The knowledge of this potential core region could be helpful in the genetic counselling of patients with 3p proximal deletions, especially concerning their phenotype.


Asunto(s)
Deleción Cromosómica , Cromosomas Humanos Par 3 , Gemelos Monocigóticos/genética , Anomalías Múltiples/diagnóstico , Anomalías Múltiples/genética , Adolescente , Preescolar , Mapeo Cromosómico , Hibridación Genómica Comparativa , Facies , Humanos , Masculino , Fenotipo
9.
Neuropediatrics ; 44(5): 268-71, 2013 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-23436495

RESUMEN

Terminal deletions of chromosome 3p26.3 confined to the CHL1 gene have previously been described in children with intellectual disability and epilepsy. Here, we report for the first time, a 3p26.3 duplication including only the CHL1 gene in an intellectually disabled girl with epilepsy. The penetrance of both deletions and duplications in 3p26.3 is reduced because all chromosomal imbalances were inherited from healthy parents. Further studies are needed to specify the pathogenic mechanism of 3p26.3 imbalances and to estimate recurrence risks in genetic counseling. However, the description of both deletions and duplications of chromosome 3p26.3 in nonsyndromic intellectual disability suggests that CHL1 is a dosage-sensitive gene with an important role for normal cognitive development.


Asunto(s)
Moléculas de Adhesión Celular/genética , Cognición/fisiología , Epilepsia/genética , Discapacidad Intelectual/genética , Adolescente , Duplicación Cromosómica , Epilepsia/complicaciones , Femenino , Humanos , Discapacidad Intelectual/complicaciones , Fenotipo
10.
BMC Urol ; 13: 3, 2013 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-23320739

RESUMEN

BACKGROUND: Papillary renal cell carcinoma is a rare cancer. Some cases can be attributed to individuals with hereditary renal cell carcinomas usually consisting of the clear cell subtype. In addition, two syndromes with hereditary papillary renal cell carcinoma have been described. One is the hereditary leiomyomatosis and renal cell carcinoma, which is characterized by cutaneous and uterine leiomyomas and renal cell carcinoma mostly consisting of the papillary renal cell carcinoma type II with a worse prognosis. CASE PRESENTATION: We describe a case of a 30-year-old woman with hereditary leiomyomatosis and renal cell carcinoma syndrome with extensively metastasized papillary renal cell carcinoma, primarily diagnosed in a cervical lymph node lacking leiomyomas at any site. CONCLUSION: Papillary renal cell carcinoma in young patients should be further investigated for a hereditary variant like the hereditary leiomyomatosis and renal cell carcinoma even if leiomyomas could not be detected. A detailed histological examination and search for mutations is essential for the survival of patients and relatives.


Asunto(s)
Carcinoma de Células Renales/secundario , Neoplasias Renales/secundario , Ganglios Linfáticos/patología , Neoplasias Primarias Múltiples/genética , Adulto , Biopsia , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/patología , Femenino , Fumarato Hidratasa/genética , Predisposición Genética a la Enfermedad , Humanos , Neoplasias Renales/genética , Neoplasias Renales/patología , Leiomiomatosis/genética , Leiomiomatosis/patología , Metástasis Linfática , Mutación Missense , Cuello , Síndromes Neoplásicos Hereditarios/genética , Síndromes Neoplásicos Hereditarios/patología , Neoplasias Cutáneas , Neoplasias Uterinas
11.
Am J Med Genet A ; 158A(2): 429-33, 2012 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-22246919

RESUMEN

Interstitial deletions of the distal part of chromosome 2p are rare, with only six reported cases involving regions from 2p23 to 2pter. Most of these were cytogenetic investigations. We describe a 14-year-old boy with an 8.97 Mb deletion of 2p23.3-24.3 detected by array comparative genomic hybridization (array CGH) who had intellectual disability (ID), unusual facial features, cryptorchidism, skeletal myopathy, dilated cardiomyopathy (DCM), and postnatal overgrowth (macrocephaly and tall stature). We compared the clinical features of the present case to previously described patients with an interstitial deletion within this chromosomal region and conclude that our patient exhibits a markedly different phenotype. Additional patients are needed to further delineate phenotype-genotype correlations.


Asunto(s)
Deleción Cromosómica , Cromosomas Humanos Par 2/genética , Estudios de Asociación Genética , Adolescente , Trastorno Dismórfico Corporal/diagnóstico , Trastorno Dismórfico Corporal/genética , Trastorno Dismórfico Corporal/patología , Cardiomiopatía Dilatada/diagnóstico , Cardiomiopatía Dilatada/genética , Cardiomiopatía Dilatada/patología , Hibridación Genómica Comparativa , Humanos , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/genética , Discapacidad Intelectual/patología , Masculino , Enfermedades Musculares/diagnóstico , Enfermedades Musculares/genética , Enfermedades Musculares/patología
12.
Am J Med Genet A ; 158A(1): 229-35, 2012 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-22140031

RESUMEN

Interstitial deletions of the proximal chromosome 16q are rare. To date, only six cases with molecularly well-characterized microdeletions within this chromosomal region have been described. We report on a patient with severe psychomotor delay, dysmorphic features, microcephaly and hypoplasia of the corpus callosum, epilepsy, a heart defect, and pronounced muscular hypotonia. Array comparative genomic hybridization (aCGH) revealed that the patient's features were likely caused by a 4.7 Mb de novo deletion on chromosome 16q12.1q12.2, which was confirmed by quantitative real-time PCR (qPCR). The psychomotor delay and craniofacial dysmorphism are more severe in our patient than previously reported patients. Unmasked recessive mutations in the ZNF423 and FTO genes on the remaining allele were excluded as the putative cause for this severe phenotype. In conclusion, the phenotypic spectrum of microdeletions in 16q12 is broad and comprises variable degrees of psychomotor delay and intellectual disability, craniofacial anomalies, and additional features, including heart defects, brain malformations, and limb anomalies.


Asunto(s)
Encéfalo/anomalías , Deleción Cromosómica , Anomalías Craneofaciales/genética , Cardiopatías Congénitas/genética , Discapacidad Intelectual/genética , Deformidades Congénitas de las Extremidades/genética , Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato , Cromosomas Humanos Par 16/genética , Hibridación Genómica Comparativa , Extremidades/anatomía & histología , Humanos , Lactante , Masculino , Microcefalia/genética , Hipotonía Muscular/genética , Fenotipo , Proteínas/genética , Reacción en Cadena en Tiempo Real de la Polimerasa
13.
Am J Med Genet A ; 158A(3): 652-8, 2012 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-22315187

RESUMEN

Noonan syndrome (NS) is a common autosomal dominant condition characterized by short stature, congenital heart defects, and dysmorphic facial features caused in approximately 50% of cases by missense mutations in the PTPN11 gene. NS patients are predisposed to malignancies including myeloproliferative disorders or leukemias. We report a female NS patient carrying a PTPN11 germline mutation c.417 G > C (p.E139D), who developed in her second year of life an acute lymphoblastic leukemia (ALL) and after remission, she developed at 4 years of age a juvenile myelomonocytic leukemia (JMML). Molecular genetic analysis of lymphoblastic blasts at the time of the ALL diagnosis revealed the germline mutation in a heterozygous state, while in the myelomonocytic blasts occurring with JMML diagnosis, the mutation p.E139D was found in a homozygous state due to a uniparental disomy (UPD). These findings lead to the suggestion that the pathogenesis of ALL and JMML in our patient is due to different mechanisms including somatically acquired secondary chromosomal abnormalities.


Asunto(s)
Mutación de Línea Germinal , Leucemia Mielomonocítica Juvenil/complicaciones , Síndrome de Noonan/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicaciones , Proteína Tirosina Fosfatasa no Receptora Tipo 11/genética , Hibridación Genómica Comparativa , Femenino , Heterocigoto , Humanos , Lactante , Leucemia Mielomonocítica Juvenil/genética , Síndrome de Noonan/complicaciones , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética
14.
Genes (Basel) ; 13(2)2022 01 19.
Artículo en Inglés | MEDLINE | ID: mdl-35205214

RESUMEN

We report a family with heterozygous deletion of exons 3-6 of the LMNA gene. The main presentation of affected family members was characterized by ventricular and supraventricular arrhythmias, atrioventricular (AV) block and sudden cardiac death (SCD) but also by severe dilative cardiomyopathy (DCM). We report on two siblings, a 36-year-old female and her 40-year-old brother, who suffer from heart failure with mildly reduced ejection fraction, AV conduction delays and premature ventricular complexes. Their 65-year-old mother underwent heart transplantation at the age of 55 due to advanced heart failure. Originally, the LMNA mutation was detected in one of the uncles. This index patient and three of his brothers died of SCD as well as their father and aunt. The two siblings were treated with implanted defibrillators in our specialized tertiary heart failure center. This case report places this specific genetic variant in the context of LMNA-associated familial DCM.


Asunto(s)
Cardiomiopatía Dilatada , Insuficiencia Cardíaca , Adulto , Anciano , Muerte Súbita Cardíaca/etiología , Femenino , Humanos , Lamina Tipo A/genética , Masculino , Mutación
15.
Am J Med Genet A ; 155A(8): 2003-7, 2011 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-21739600

RESUMEN

Alterations of the Fragile Mental Retardation 2 gene (FMR2, synonym AFF2) can result in non-specific, mild to borderline X-linked intellectual disability (XLID), and behavioral problems. The well-known molecular pathomechanism of this condition, also referred to as FRAXE, is a (CCG)(n) trinucleotide repeat expansion which leads to silencing of the FMR2 gene. However, deletions within the FMR2 gene may also be causative of the disorder. Here, we report on two brothers diagnosed with FRAXE in whom a small deletion in the FMR2 gene was detected by whole genome array comparative genomic hybridization (CGH). The deletion was also present in their clinically healthy mother and maternal uncle who was similarly affected, but not in a healthy older brother of the two patients. Our observation demonstrates that FMR2 gene deletions may contribute to the FRAXE phenotype. Therefore, we suggest that screening for FMR2 gene deletions using array CGH should be considered in patients with non-specific XLID and absent trinucleotide expansion.


Asunto(s)
Trastorno Autístico/genética , Cromosomas Humanos X/genética , Síndrome del Cromosoma X Frágil/genética , Eliminación de Gen , Proteínas Nucleares/genética , Niño , Hibridación Genómica Comparativa , Síndrome del Cromosoma X Frágil/diagnóstico , Estudios de Asociación Genética , Humanos , Masculino
16.
Diagnostics (Basel) ; 11(6)2021 Jun 04.
Artículo en Inglés | MEDLINE | ID: mdl-34199854

RESUMEN

Generalized Arterial Calcification of Infancy (GACI) is a rare disease inherited in a recessive manner, with severe and diffuse early onset of calcifications along the internal elastic lamina in large and medium size arteries. The diagnosis results are from clinical manifestations, imaging, histopathologic exams, and genetic tests. GACI is predominantly caused by biallelic pathogenic variant in the ENPP1 gene (GACI1, OMIM#208000) and, to a lesser extent, by pathogenic variants in the ABCC6 gene (GACI2, OMIM#614473). We present a novel variation in the ENPP1 gene identified in a patient clinically diagnosed with GACI and confirmed by genetic investigation and autopsy as GACI type 1. The sequence analysis of the patient's ENPP1 gene detected two heterozygous variants c.1412A>G (p.Tyr471Cys) and c.1715T>C (p.Leu572Ser). The variant c.1715T>C (p.Leu572Ser) has not been described yet in the literature and in mutation databases. A genetic analysis was also carried out for the parents of the newborn; the heterozygous pathogenic variant c.1412A>G (p.Tyr471Cys) was detected in the mother's ENPP1 gene, and a sequence analysis of the father's ENPP1 gene revealed the novel heterozygous variant c.1715T>C (p.Leu572Ser). Our results showed that the variant c.1715T>C (p.Leu572Ser) may have a pathogenic role in the development of GACI type1 (GACI1, OMIM#208000), at least when associated with the pathogenic c.1412A>G (p.Tyr471Cys) variant. The identification of novel mutations potentially enabled genotype/phenotype associations that will ultimately have an impact on clinical management and prognosis for the disease.

17.
Sci Immunol ; 6(57)2021 03 12.
Artículo en Inglés | MEDLINE | ID: mdl-33712472

RESUMEN

Epigenetic landscapes can provide insight into regulation of gene expression and cellular diversity. Here, we examined the transcriptional and epigenetic profiles of seven human blood natural killer (NK) cell populations, including adaptive NK cells. The BCL11B gene, encoding a transcription factor (TF) essential for T cell development and function, was the most extensively regulated, with expression increasing throughout NK cell differentiation. Several Bcl11b-regulated genes associated with T cell signaling were specifically expressed in adaptive NK cell subsets. Regulatory networks revealed reciprocal regulation at distinct stages of NK cell differentiation, with Bcl11b repressing RUNX2 and ZBTB16 in canonical and adaptive NK cells, respectively. A critical role for Bcl11b in driving NK cell differentiation was corroborated in BCL11B-mutated patients and by ectopic Bcl11b expression. Moreover, Bcl11b was required for adaptive NK cell responses in a murine cytomegalovirus model, supporting expansion of these cells. Together, we define the TF regulatory circuitry of human NK cells and uncover a critical role for Bcl11b in promoting NK cell differentiation and function.


Asunto(s)
Diferenciación Celular/inmunología , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Proteínas Represoras/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Animales , Biomarcadores , Diferenciación Celular/genética , Preescolar , Ensamble y Desensamble de Cromatina , Elementos de Facilitación Genéticos , Epigénesis Genética , Regulación de la Expresión Génica , Antígenos HLA/genética , Antígenos HLA/inmunología , Humanos , Inmunofenotipificación , Lactante , Células Asesinas Naturales/citología , Ratones , Ratones Noqueados , Receptores KIR/genética , Receptores KIR/metabolismo , Proteínas Represoras/genética , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Transcriptoma , Proteínas Supresoras de Tumor/genética
18.
Hum Mutat ; 31(5): 617-21, 2010 May.
Artículo en Inglés | MEDLINE | ID: mdl-20186691

RESUMEN

An autosomal recessive form of hereditary spastic paraplegia (AR-HSP) is primarily caused by mutations in the SPG7 gene, which codes for paraplegin, a subunit of the hetero-oligomeric m-AAA protease in mitochondria. In the current study, sequencing of the SPG7 gene in the genomic DNA of 25 unrelated HSP individuals/families led to the identification of two HSP patients with compound heterozygous mutations (p.G349S/p.W583C and p.A510V/p.N739KfsX741) in the coding sequence of the SPG7 gene. We used a yeast complementation assay to evaluate the functional consequence of novel SPG7 sequence variants detected in the HSP patients. We assessed the proteolytic activity of hetero-oligomeric m-AAA proteases composed of paraplegin variant(s) and proteolytically inactive forms of AFG3L2 (AFG3L2(E575Q) or AFG3L2(K354A)) upon expression in m-AAA protease-deficient yeast cells. We demonstrate that the newly identified paraplegin variants perturb the proteolytic function of hetero-oligomeric m-AAA protease. Moreover, commonly occurring silent polymorphisms such as p.T503A and p.R688Q could be distinguished from mutations (p.G349S, p.W583C, p.A510V, and p.N739KfsX741) in our HSP cohort. The yeast complementation assay thus can serve as a reliable system to distinguish a pathogenic mutation from a silent polymorphism for any novel SPG7 sequence variant, which will facilitate the interpretation of genetic data for SPG7.


Asunto(s)
Análisis Mutacional de ADN/métodos , Metaloendopeptidasas/genética , Saccharomyces cerevisiae/metabolismo , Paraplejía Espástica Hereditaria/genética , Proteasas ATP-Dependientes , ATPasas Asociadas con Actividades Celulares Diversas , Adenosina Trifosfatasas/genética , Humanos , Polimorfismo Genético , Saccharomyces cerevisiae/genética , Paraplejía Espástica Hereditaria/diagnóstico , Paraplejía Espástica Hereditaria/metabolismo
19.
Swiss Med Wkly ; 138(29-30): 432-6, 2008 Jul 26.
Artículo en Inglés | MEDLINE | ID: mdl-18654869

RESUMEN

UNLABELLED: Hereditary haemorrhagic telangiectasia (HHT), associated with arteriovenous malformations, is a genetic disease of the vascular system with a frequency of approx. 1:10,000. Genetic diagnosis serves to identify individuals at risk of developing the disease and is a useful tool for genetic counselling purposes. QUESTIONS UNDER STUDY: Here we report on a child presenting severe arteriovenous malformations leading to heart failure. Her mother and grandmother present fewer symptoms of hereditary haemorrhagic telangiectasia. In this study we identify the cause of HHT in the family. METHODS: Clinical examination, PCR, DNA sequencing, quantitative PCR, Southern blot, xray, ultrasound, cardiac catheterisation and angiocardiography. RESULTS: Initially the sequence variant in c.392C>T in the endoglin gene was detected in the grandmother, but not in other affected family members. Further analyses revealed a deletion of exon 1 of endoglin, segregating with the phenotype. CONCLUSIONS: This report points out the need for careful evaluation of molecular genetic findings, particularly in diseases with highly variable phenotype.


Asunto(s)
Fenotipo , Telangiectasia Hemorrágica Hereditaria/fisiopatología , Técnicas de Laboratorio Clínico , ADN/sangre , ADN/aislamiento & purificación , Alemania , Humanos , Lactante , Índice de Severidad de la Enfermedad , Telangiectasia Hemorrágica Hereditaria/complicaciones , Telangiectasia Hemorrágica Hereditaria/diagnóstico , Telangiectasia Hemorrágica Hereditaria/etiología , Telangiectasia Hemorrágica Hereditaria/genética
20.
J Exp Med ; 215(5): 1327-1336, 2018 05 07.
Artículo en Inglés | MEDLINE | ID: mdl-29636373

RESUMEN

Ubiquitously expressed Cbl-interacting protein of 85 kD (CIN85) is a multifunctional adapter molecule supposed to regulate numerous cellular processes that are critical for housekeeping as well as cell type-specific functions. However, limited information exists about the in vivo roles of CIN85, because only conditional mouse mutants with cell type-specific ablation of distinct CIN85 isoforms in brain and B lymphocytes have been generated so far. No information is available about the roles of CIN85 in humans. Here, we report on primary antibody deficiency in patients harboring a germline deletion within the CIN85 gene on the X chromosome. In the absence of CIN85, all immune cell compartments developed normally, but B lymphocytes showed intrinsic defects in distinct effector pathways of the B cell antigen receptor, most notably NF-κB activation and up-regulation of CD86 expression on the cell surface. These results reveal nonredundant functions of CIN85 for humoral immune responses.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Anticuerpos/metabolismo , Cromosomas Humanos X/genética , Eliminación de Gen , Células Germinativas/metabolismo , Síndromes de Inmunodeficiencia/genética , Proteínas Adaptadoras Transductoras de Señales/deficiencia , Linfocitos B/inmunología , Calcio/metabolismo , Humanos , Inmunoglobulina G/sangre , Síndromes de Inmunodeficiencia/sangre , Inmunofenotipificación , Activación de Linfocitos/inmunología , Masculino , FN-kappa B/metabolismo , Receptores de Antígenos de Linfocitos T/metabolismo , Hermanos , Transducción de Señal
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