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1.
J Med Genet ; 60(12): 1224-1234, 2023 Nov 27.
Artículo en Inglés | MEDLINE | ID: mdl-37586838

RESUMEN

BACKGROUND: KBG syndrome is caused by haploinsufficiency of ANKRD11 and is characterised by macrodontia of upper central incisors, distinctive facial features, short stature, skeletal anomalies, developmental delay, brain malformations and seizures. The central nervous system (CNS) and skeletal features remain poorly defined. METHODS: CNS and/or skeletal imaging were collected from molecularly confirmed individuals with KBG syndrome through an international network. We evaluated the original imaging and compared our results with data in the literature. RESULTS: We identified 53 individuals, 44 with CNS and 40 with skeletal imaging. Common CNS findings included incomplete hippocampal inversion and posterior fossa malformations; these were significantly more common than previously reported (63.4% and 65.9% vs 1.1% and 24.7%, respectively). Additional features included patulous internal auditory canal, never described before in KBG syndrome, and the recurrence of ventriculomegaly, encephalic cysts, empty sella and low-lying conus medullaris. We found no correlation between these structural anomalies and epilepsy or intellectual disability. Prevalent skeletal findings comprised abnormalities of the spine including scoliosis, coccygeal anomalies and cervical ribs. Hand X-rays revealed frequent abnormalities of carpal bone morphology and maturation, including a greater delay in ossification compared with metacarpal/phalanx bones. CONCLUSION: This cohort enabled us to describe the prevalence of very heterogeneous neuroradiological and skeletal anomalies in KBG syndrome. Knowledge of the spectrum of such anomalies will aid diagnostic accuracy, improve patient care and provide a reference for future research on the effects of ANKRD11 variants in skeletal and brain development.


Asunto(s)
Anomalías Múltiples , Enfermedades del Desarrollo Óseo , Discapacidad Intelectual , Anomalías Dentarias , Humanos , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/genética , Anomalías Múltiples/diagnóstico , Anomalías Múltiples/genética , Enfermedades del Desarrollo Óseo/diagnóstico por imagen , Enfermedades del Desarrollo Óseo/genética , Anomalías Dentarias/diagnóstico por imagen , Anomalías Dentarias/genética , Facies , Fenotipo , Proteínas Represoras/genética , Factores de Transcripción , Neuroimagen
2.
J Inherit Metab Dis ; 46(2): 326-334, 2023 03.
Artículo en Inglés | MEDLINE | ID: mdl-36719165

RESUMEN

Congenital disorders of glycosylation (CDG) and Niemann-Pick type C (NPC) disease are inborn errors of metabolism that can both present with infantile-onset severe liver disease and other multisystemic manifestations. Plasma bile acid and N-palmitoyl-O-phosphocholineserine (PPCS) are screening biomarkers with proposed improved sensitivity and specificity for NPC. We report an infant with ATP6AP1-CDG who presented with cholestatic liver failure and elevated plasma oxysterols and bile acid, mimicking NPC clinically and biochemically. On further investigation, PPCS, but not the bile acid derivative N-(3ß,5α,6ß-trihydroxy-cholan-24-oyl) glycine (TCG), were elevated in plasma samples from individuals with ATP6AP1-, ALG1-, ALG8-, and PMM2-CDG. These findings highlight the importance of keeping CDG within the diagnostic differential when evaluating children with early onset severe liver disease and elevated bile acid or PPCS to prevent delayed diagnosis and treatment.


Asunto(s)
Trastornos Congénitos de Glicosilación , Enfermedad de Niemann-Pick Tipo C , Oxiesteroles , ATPasas de Translocación de Protón Vacuolares , Lactante , Niño , Humanos , Glicosilación , Ácidos y Sales Biliares , Hidrolasas
3.
J Med Genet ; 2022 Jul 05.
Artículo en Inglés | MEDLINE | ID: mdl-35790351

RESUMEN

PURPOSE: To summarise the clinical, molecular and biochemical phenotype of mannosyl-oligosaccharide glucosidase-related congenital disorders of glycosylation (MOGS-CDG), which presents with variable clinical manifestations, and to analyse which clinical biochemical assay consistently supports diagnosis in individuals with bi-allelic variants in MOGS. METHODS: Phenotypic characterisation was performed through an international and multicentre collaboration. Genetic testing was done by exome sequencing and targeted arrays. Biochemical assays on serum and urine were performed to delineate the biochemical signature of MOGS-CDG. RESULTS: Clinical phenotyping revealed heterogeneity in MOGS-CDG, including neurological, immunological and skeletal phenotypes. Bi-allelic variants in MOGS were identified in 12 individuals from 11 families. The severity in each organ system was variable, without definite genotype correlation. Urine oligosaccharide analysis was consistently abnormal for all affected probands, whereas other biochemical analyses such as serum transferrin analysis was not consistently abnormal. CONCLUSION: The clinical phenotype of MOGS-CDG includes multisystemic involvement with variable severity. Molecular analysis, combined with biochemical testing, is important for diagnosis. In MOGS-CDG, urine oligosaccharide analysis via matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry can be used as a reliable biochemical test for screening and confirmation of disease.

4.
Am J Hum Genet ; 103(4): 553-567, 2018 10 04.
Artículo en Inglés | MEDLINE | ID: mdl-30290151

RESUMEN

The conserved oligomeric Golgi (COG) complex is involved in intracellular vesicular transport, and is composed of eight subunits distributed in two lobes, lobe A (COG1-4) and lobe B (COG5-8). We describe fourteen individuals with Saul-Wilson syndrome, a rare form of primordial dwarfism with characteristic facial and radiographic features. All affected subjects harbored heterozygous de novo variants in COG4, giving rise to the same recurrent amino acid substitution (p.Gly516Arg). Affected individuals' fibroblasts, whose COG4 mRNA and protein were not decreased, exhibited delayed anterograde vesicular trafficking from the ER to the Golgi and accelerated retrograde vesicular recycling from the Golgi to the ER. This altered steady-state equilibrium led to a decrease in Golgi volume, as well as morphologic abnormalities with collapse of the Golgi stacks. Despite these abnormalities of the Golgi apparatus, protein glycosylation in sera and fibroblasts from affected subjects was not notably altered, but decorin, a proteoglycan secreted into the extracellular matrix, showed altered Golgi-dependent glycosylation. In summary, we define a specific heterozygous COG4 substitution as the molecular basis of Saul-Wilson syndrome, a rare skeletal dysplasia distinct from biallelic COG4-CDG.


Asunto(s)
Síndrome del Cromosoma X Frágil/genética , Transporte de Proteínas/genética , Proteoglicanos/genética , Proteínas de Transporte Vesicular/genética , Adulto , Sustitución de Aminoácidos/genética , Animales , Animales Modificados Genéticamente/genética , Línea Celular , Niño , Preescolar , Retículo Endoplásmico/genética , Matriz Extracelular/genética , Femenino , Fibroblastos/patología , Glicosilación , Aparato de Golgi/genética , Heterocigoto , Humanos , Lactante , Masculino , Pez Cebra
5.
J Neurogenet ; 35(2): 74-83, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33970744

RESUMEN

KCTD7 is a member of the potassium channel tetramerization domain-containing protein family and has been associated with progressive myoclonic epilepsy (PME), characterized by myoclonus, epilepsy, and neurological deterioration. Here we report four affected individuals from two unrelated families in which we identified KCTD7 compound heterozygous single nucleotide variants through exome sequencing. RNAseq was used to detect a non-annotated splicing junction created by a synonymous variant in the second family. Whole-cell patch-clamp analysis of neuroblastoma cells overexpressing the patients' variant alleles demonstrated aberrant potassium regulation. While all four patients experienced many of the common clinical features of PME, they also showed variable phenotypes not previously reported, including dysautonomia, brain pathology findings including a significantly reduced thalamus, and the lack of myoclonic seizures. To gain further insight into the pathogenesis of the disorder, zinc finger nucleases were used to generate kctd7 knockout zebrafish. Kctd7 homozygous mutants showed global dysregulation of gene expression and increased transcription of c-fos, which has previously been correlated with seizure activity in animal models. Together these findings expand the known phenotypic spectrum of KCTD7-associated PME, report a new animal model for future studies, and contribute valuable insights into the disease.


Asunto(s)
Epilepsias Mioclónicas Progresivas/genética , Canales de Potasio/genética , Animales , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Mutación , Epilepsias Mioclónicas Progresivas/fisiopatología , Linaje , Fenotipo , Pez Cebra
6.
Hum Mol Genet ; 27(4): 691-705, 2018 02 15.
Artículo en Inglés | MEDLINE | ID: mdl-29300972

RESUMEN

UBTF (upstream binding transcription factor) exists as two isoforms; UBTF1 regulates rRNA transcription by RNA polymerase 1, whereas UBTF2 regulates mRNA transcription by RNA polymerase 2. Herein, we describe 4 patients with very similar patterns of neuroregression due to recurrent de novo mutations in UBTF (GRCh37/hg19, NC_000017.10: g.42290219C > T, NM_014233.3: c.628G > A) resulting in the same amino acid change in both UBTF1 and UBTF2 (p.Glu210Lys [p.E210K]). Disease onset in our cohort was at 2.5 to 3 years and characterized by slow progression of global motor, cognitive and behavioral dysfunction. Notable early features included hypotonia with a floppy gait, high-pitched dysarthria and hyperactivity. Later features included aphasia, dystonia, and spasticity. Speech and ambulatory ability were lost by the early teens. Magnetic resonance imaging showed progressive generalized cerebral atrophy (supratentorial > infratentorial) with involvement of both gray and white matter. Patient fibroblasts showed normal levels of UBTF transcripts, increased expression of pre-rRNA and 18S rRNA, nucleolar abnormalities, markedly increased numbers of DNA breaks, defective cell-cycle progression, and apoptosis. Expression of mutant human UBTF1 in Drosophila neurons was lethal. Although no loss-of-function variants are reported in the Exome Aggregation Consortium (ExAC) database and Ubtf-/- is early embryonic lethal in mice, Ubtf+/- mice displayed only mild motor and behavioral dysfunction in adulthood. Our data underscore the importance of including UBTF E210K in the differential diagnosis of neuroregression and suggest that mainly gain-of-function mechanisms contribute to the pathogenesis of the UBTF E210K neuroregression syndrome.


Asunto(s)
Mutación Missense/genética , Proteínas del Complejo de Iniciación de Transcripción Pol1/genética , Preescolar , Disartria/genética , Femenino , Ataxia de la Marcha/genética , Humanos , Imagen por Resonancia Magnética , Masculino , Hipotonía Muscular/genética , Linaje , ARN Ribosómico 18S/genética
7.
Genet Med ; 22(10): 1598-1605, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-32461667

RESUMEN

PURPOSE: Pathogenic autosomal recessive variants in CAD, encoding the multienzymatic protein initiating pyrimidine de novo biosynthesis, cause a severe inborn metabolic disorder treatable with a dietary supplement of uridine. This condition is difficult to diagnose given the large size of CAD with over 1000 missense variants and the nonspecific clinical presentation. We aimed to develop a reliable and discerning assay to assess the pathogenicity of CAD variants and to select affected individuals that might benefit from uridine therapy. METHODS: Using CRISPR/Cas9, we generated a human CAD-knockout cell line that requires uridine supplements for survival. Transient transfection of the knockout cells with recombinant CAD restores growth in absence of uridine. This system determines missense variants that inactivate CAD and do not rescue the growth phenotype. RESULTS: We identified 25 individuals with biallelic variants in CAD and a phenotype consistent with a CAD deficit. We used the CAD-knockout complementation assay to test a total of 34 variants, identifying 16 as deleterious for CAD activity. Combination of these pathogenic variants confirmed 11 subjects with a CAD deficit, for whom we describe the clinical phenotype. CONCLUSIONS: We designed a cell-based assay to test the pathogenicity of CAD variants, identifying 11 CAD-deficient individuals who could benefit from uridine therapy.


Asunto(s)
Aspartato Carbamoiltransferasa , Carbamoil-Fosfato Sintasa (Glutamina-Hidrolizante) , Línea Celular , Dihidroorotasa , Humanos , Uridina
8.
Genet Med ; 22(5): 857-866, 2020 05.
Artículo en Inglés | MEDLINE | ID: mdl-31949312

RESUMEN

PURPOSE: Four patients with Saul-Wilson syndrome were reported between 1982 and 1994, but no additional individuals were described until 2018, when the molecular etiology of the disease was elucidated. Hence, the clinical phenotype of the disease remains poorly defined. We address this shortcoming by providing a detailed characterization of its phenotype. METHODS: Retrospective chart reviews were performed and primary radiographs assessed for all 14 individuals. Four individuals underwent detailed ophthalmologic examination by the same physician. Two individuals underwent gynecologic evaluation. Z-scores for height, weight, head circumference and body mass index were calculated at different ages. RESULTS: All patients exhibited short stature, with sharp decline from the mean within the first months of life, and a final height Z-score between -4 and -8.5 standard deviations. The facial and radiographic features evolved over time. Intermittent neutropenia was frequently observed. Novel findings included elevation of liver transaminases, skeletal fragility, rod-cone dystrophy, and cystic macular changes. CONCLUSIONS: Saul-Wilson syndrome presents a remarkably uniform phenotype, and the comprehensive description of our cohort allows for improved understanding of the long-term morbidity of the condition, establishment of follow-up recommendations for affected individuals, and documentation of the natural history into adulthood for comparison with treated patients, when therapeutics become available.


Asunto(s)
Enanismo , Adulto , Femenino , Humanos , Fenotipo , Estudios Retrospectivos
9.
Mol Genet Metab ; 130(1): 49-57, 2020 05.
Artículo en Inglés | MEDLINE | ID: mdl-32165008

RESUMEN

BACKGROUND: Mutations in the ARV1 Homolog, Fatty Acid Homeostasis Modulator (ARV1), have recently been described in association with early infantile epileptic encephalopathy 38. Affected individuals presented with epilepsy, ataxia, profound intellectual disability, visual impairment, and central hypotonia. In S. cerevisiae, Arv1 is thought to be involved in sphingolipid metabolism and glycophosphatidylinositol (GPI)-anchor synthesis. The function of ARV1 in human cells, however, has not been elucidated. METHODS: Mutations were discovered through whole exome sequencing and alternate splicing was validated on the cDNA level. Expression of the variants was determined by qPCR and Western blot. Expression of GPI-anchored proteins on neutrophils and fibroblasts was analyzed by FACS and immunofluorescence microscopy, respectively. RESULTS: Here we describe seven patients from two unrelated families with biallelic splice mutations in ARV1. The patients presented with early onset epilepsy, global developmental delays, profound hypotonia, delayed speech development, cortical visual impairment, and severe generalized cerebral and cerebellar atrophy. The splice variants resulted in decreased ARV1 expression and significant decreases in GPI-anchored protein on the membranes of neutrophils and fibroblasts, indicating that the loss of ARV1 results in impaired GPI-anchor synthesis. CONCLUSION: Loss of GPI-anchored proteins on our patients' cells confirms that the yeast Arv1 function of GPI-anchor synthesis is conserved in humans. Overlap between the phenotypes in our patients and those reported for other GPI-anchor disorders suggests that ARV1-deficiency is a GPI-anchor synthesis disorder.


Asunto(s)
Anomalías Múltiples/genética , Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , Discapacidades del Desarrollo/genética , Epilepsia/genética , Glicosilfosfatidilinositoles/deficiencia , Discapacidad Intelectual/genética , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Anomalías Múltiples/fisiopatología , Adolescente , Empalme Alternativo/genética , Preescolar , Discapacidades del Desarrollo/fisiopatología , Epilepsia/fisiopatología , Femenino , Fibroblastos/metabolismo , Proteínas Ligadas a GPI/metabolismo , Glicosilfosfatidilinositoles/biosíntesis , Homocigoto , Humanos , Lactante , Recién Nacido , Masculino , Mutación , Neutrófilos/metabolismo , Linaje , Secuenciación del Exoma
10.
Am J Med Genet A ; 182(5): 1278-1283, 2020 05.
Artículo en Inglés | MEDLINE | ID: mdl-32150337

RESUMEN

Waardenburg syndrome (WS) is a group of genetic disorders associated with varying components of sensorineural hearing loss and abnormal pigmentation of the hair, skin, and eyes. There exist four different WS subtypes, each defined by the absence or presence of additional features. One of the genes associated with WS is SOX10, a key transcription factor for the development of neural crest-derived lineages. Here we report a 12-year-old boy with a novel de novo SOX10 frameshift mutation and unique combination of clinical features including primary peripheral demyelinating neuropathy, hearing loss and visual impairment but absence of Hirschsprung disease and the typical pigmentary changes of hair or skin. This expands the spectrum of currently recognized phenotypes associated with WS and illustrates the phenotypic heterogeneity of SOX10-associated WS.


Asunto(s)
Predisposición Genética a la Enfermedad , Enfermedad de Hirschsprung/genética , Factores de Transcripción SOXE/genética , Síndrome de Waardenburg/genética , Enfermedades Autoinmunes del Sistema Nervioso/genética , Enfermedades Autoinmunes del Sistema Nervioso/fisiopatología , Niño , Enfermedades Desmielinizantes/genética , Enfermedades Desmielinizantes/fisiopatología , Mutación del Sistema de Lectura/genética , Enfermedad de Hirschsprung/fisiopatología , Humanos , Masculino , Linaje , Fenotipo , Síndrome de Waardenburg/fisiopatología
11.
Epilepsia ; 61(6): 1142-1155, 2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-32452540

RESUMEN

OBJECTIVE: To define the phenotypic spectrum of phosphatidylinositol glycan class A protein (PIGA)-related congenital disorder of glycosylation (PIGA-CDG) and evaluate genotype-phenotype correlations. METHODS: Our cohort encompasses 40 affected males with a pathogenic PIGA variant. We performed a detailed phenotypic assessment, and in addition, we reviewed the available clinical data of 36 previously published cases and assessed the variant pathogenicity using bioinformatical approaches. RESULTS: Most individuals had hypotonia, moderate to profound global developmental delay, and intractable seizures. We found that PIGA-CDG spans from a pure neurological phenotype at the mild end to a Fryns syndrome-like phenotype. We found a high frequency of cardiac anomalies including structural anomalies and cardiomyopathy, and a high frequency of spontaneous death, especially in childhood. Comparative bioinformatical analysis of common variants, found in the healthy population, and pathogenic variants, identified in affected individuals, revealed a profound physiochemical dissimilarity of the substituted amino acids in variant constrained regions of the protein. SIGNIFICANCE: Our comprehensive analysis of the largest cohort of published and novel PIGA patients broadens the spectrum of PIGA-CDG. Our genotype-phenotype correlation facilitates the estimation on pathogenicity of variants with unknown clinical significance and prognosis for individuals with pathogenic variants in PIGA.


Asunto(s)
Variación Genética/genética , Hernia Diafragmática/diagnóstico por imagen , Hernia Diafragmática/genética , Deformidades Congénitas de las Extremidades/diagnóstico por imagen , Deformidades Congénitas de las Extremidades/genética , Proteínas de la Membrana/genética , Adulto , Secuencia de Aminoácidos , Niño , Estudios de Cohortes , Electroencefalografía/métodos , Facies , Hernia Diafragmática/fisiopatología , Humanos , Recién Nacido , Deformidades Congénitas de las Extremidades/fisiopatología , Imagen por Resonancia Magnética/métodos , Masculino
12.
J Inherit Metab Dis ; 43(5): 1037-1045, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32395830

RESUMEN

The transmembrane domain recognition complex (TRC) targets cytoplasmic C-terminal tail-anchored (TA) proteins to their respective membranes in the endoplasmic reticulum (ER), Golgi, and mitochondria. It is composed of three proteins, GET4, BAG6, and GET5. We identified an individual with compound heterozygous missense variants (p.Arg122His, p.Ile279Met) in GET4 that reduced all three TRC proteins by 70% to 90% in his fibroblasts, suggesting a possible defect in TA protein targeting. He presented with global developmental delay, intellectual disabilities, seizures, facial dysmorphism, and delayed bone age. We found the TA protein, syntaxin 5, is poorly targeted to Golgi membranes compared to normal controls. Since GET4 regulates ER to Golgi transport, we hypothesized that such transport would be disrupted in his fibroblasts, and discovered that retrograde (but not anterograde) transport was significantly reduced. Despite reduction in the three TRC proteins, their mRNA levels were unchanged, suggesting increased degradation in patient fibroblasts. Treating fibroblasts with the FDA-approved proteasome inhibitor, bortezomib (10 nM), restored syntaxin 5 localization and nearly normalized the levels of all three TRC proteins. Our study identifies the first individual with GET4 mutations.


Asunto(s)
Trastornos Congénitos de Glicosilación/genética , Retículo Endoplásmico/metabolismo , Aparato de Golgi/metabolismo , Chaperonas Moleculares/genética , Niño , Humanos , Masculino , Modelos Moleculares , Mutación , Transporte de Proteínas , Transducción de Señal
13.
J Inherit Metab Dis ; 43(6): 1333-1348, 2020 11.
Artículo en Inglés | MEDLINE | ID: mdl-32681751

RESUMEN

Asparagine-linked glycosylation 13 homolog (ALG13) encodes a nonredundant, highly conserved, X-linked uridine diphosphate (UDP)-N-acetylglucosaminyltransferase required for the synthesis of lipid linked oligosaccharide precursor and proper N-linked glycosylation. De novo variants in ALG13 underlie a form of early infantile epileptic encephalopathy known as EIEE36, but given its essential role in glycosylation, it is also considered a congenital disorder of glycosylation (CDG), ALG13-CDG. Twenty-four previously reported ALG13-CDG cases had de novo variants, but surprisingly, unlike most forms of CDG, ALG13-CDG did not show the anticipated glycosylation defects, typically detected by altered transferrin glycosylation. Structural homology modeling of two recurrent de novo variants, p.A81T and p.N107S, suggests both are likely to impact the function of ALG13. Using a corresponding ALG13-deficient yeast strain, we show that expressing yeast ALG13 with either of the highly conserved hotspot variants rescues the observed growth defect, but not its glycosylation abnormality. We present molecular and clinical data on 29 previously unreported individuals with de novo variants in ALG13. This more than doubles the number of known cases. A key finding is that a vast majority of the individuals presents with West syndrome, a feature shared with other CDG types. Among these, the initial epileptic spasms best responded to adrenocorticotropic hormone or prednisolone, while clobazam and felbamate showed promise for continued epilepsy treatment. A ketogenic diet seems to play an important role in the treatment of these individuals.


Asunto(s)
Trastornos Congénitos de Glicosilación/genética , N-Acetilglucosaminiltransferasas/deficiencia , N-Acetilglucosaminiltransferasas/genética , Espasmos Infantiles/genética , Biomarcadores , Preescolar , Trastornos Congénitos de Glicosilación/diagnóstico , Dieta Cetogénica , Femenino , Glicosilación , Humanos , Lactante , Masculino , Mutación , N-Acetilglucosaminiltransferasas/química , Espasmos Infantiles/diagnóstico , Transferrina/metabolismo
14.
Hum Mutat ; 40(1): 42-47, 2019 01.
Artículo en Inglés | MEDLINE | ID: mdl-30362252

RESUMEN

The genetic etiologies of many rare disorders, including early infantile epileptic encephalopathies, are largely undiagnosed. A 6-year-old girl was admitted to the National Institutes of Health Undiagnosed Diseases Program with profound intellectual disability, infantile-onset seizures, chronic respiratory failure, facial dysmorphisms, skeletal abnormalities, and atrial septum defect. A large region of homozygosity was discovered on chromosome 16, spanning 16q22.1-16q24.3' caused by uniparental disomy (UPD) that included a maternally inherited homozygous microdeletion covering exon 6 of WWOX (NM_016373.3). mRNA expression analysis revealed that the deletion led to nonsense-mediated decay of the NM_016373.3 transcript; the exon 6 of an alternative transcript (NM_130791.3), lacking the short-chain dehydrogenase, was utilized. The microdeletion in WWOX explains the seizures and intellectual disability, while pathogenic variants in another gene, HSPG2, are likely responsible for the patient's skeletal abnormalities. This report describes a rare autosomal recessive disorder with multiple genetic etiologies, one of which involves UPD.


Asunto(s)
Deleción Cromosómica , Espasmos Infantiles/genética , Proteínas Supresoras de Tumor/genética , Disomía Uniparental/genética , Oxidorreductasa que Contiene Dominios WW/genética , Adulto , Secuencia de Bases , Niño , Cromosomas Humanos Par 16/genética , Femenino , Proteoglicanos de Heparán Sulfato/genética , Homocigoto , Humanos , Lactante , Polimorfismo de Nucleótido Simple/genética
15.
Am J Hum Genet ; 98(2): 339-46, 2016 Feb 04.
Artículo en Inglés | MEDLINE | ID: mdl-26805780

RESUMEN

Congenital disorders of glycosylation (CDGs) are disorders of abnormal protein glycosylation that affect multiple organ systems. Because most CDGs have been described in only a few individuals, our understanding of the associated phenotypes and the mechanisms of individual survival are limited. In the process of studying two siblings, aged 6 and 11 years, with MOGS-CDG and biallelic MOGS (mannosyl-oligosaccharide glucosidase) mutations (GenBank: NM_006302.2; c.[65C>A; 329G>A] p.[Ala22Glu; Arg110His]; c.[370C>T] p.[Gln124(∗)]), we noted that their survival was much longer than the previous report of MOGS-CDG, in a child who died at 74 days of age. Upon mutation analysis, we detected multiple MOGS genotypes including wild-type alleles in their cultured fibroblast and peripheral blood DNA. Further analysis of DNA from cultured fibroblasts of six individuals with compound heterozygous mutations of PMM2 (PMM2-CDG), MPI (MPI-CDG), ALG3 (ALG3-CDG), ALG12 (ALG12-CDG), DPAGT1 (DPAGT1-CDG), and ALG1 (ALG1-CDG) also identified multiple genotypes including wild-type alleles for each. Droplet digital PCR showed a ratio of nearly 1:1 wild-type to mutant alleles for most, but not all, mutations. This suggests that mitotic recombination contributes to the survival and the variable expressivity of individuals with compound heterozygous CDGs. This also provides an explanation for prior observations of a reduced frequency of homozygous mutations and might contribute to increased levels of residual enzyme activity in cultured fibroblasts of individuals with MPI- and PMM2-CDGs.


Asunto(s)
Trastornos Congénitos de Glicosilación/genética , Mitosis , Recombinación Genética , Secuencia de Aminoácidos , Niño , Femenino , Fibroblastos/metabolismo , Frecuencia de los Genes , Genoma Humano , Genotipo , Heterocigoto , Humanos , Masculino , Datos de Secuencia Molecular , Mutación , Análisis de Secuencia de ADN , Hermanos , alfa-Glucosidasas/genética , alfa-Glucosidasas/metabolismo
16.
Am J Hum Genet ; 97(1): 99-110, 2015 Jul 02.
Artículo en Inglés | MEDLINE | ID: mdl-26119818

RESUMEN

Ablepharon macrostomia syndrome (AMS) and Barber-Say syndrome (BSS) are rare congenital ectodermal dysplasias characterized by similar clinical features. To establish the genetic basis of AMS and BSS, we performed extensive clinical phenotyping, whole exome and candidate gene sequencing, and functional validations. We identified a recurrent de novo mutation in TWIST2 in seven independent AMS-affected families, as well as another recurrent de novo mutation affecting the same amino acid in ten independent BSS-affected families. Moreover, a genotype-phenotype correlation was observed, because the two syndromes differed based solely upon the nature of the substituting amino acid: a lysine at TWIST2 residue 75 resulted in AMS, whereas a glutamine or alanine yielded BSS. TWIST2 encodes a basic helix-loop-helix transcription factor that regulates the development of mesenchymal tissues. All identified mutations fell in the basic domain of TWIST2 and altered the DNA-binding pattern of Flag-TWIST2 in HeLa cells. Comparison of wild-type and mutant TWIST2 expressed in zebrafish identified abnormal developmental phenotypes and widespread transcriptome changes. Our results suggest that autosomal-dominant TWIST2 mutations cause AMS or BSS by inducing protean effects on the transcription factor's DNA binding.


Asunto(s)
Anomalías Múltiples/genética , Anomalías del Ojo/genética , Enfermedades de los Párpados/genética , Hirsutismo/genética , Hipertelorismo/genética , Hipertricosis/genética , Macrostomía/genética , Modelos Moleculares , Fenotipo , Proteínas Represoras/genética , Anomalías Cutáneas/genética , Proteína 1 Relacionada con Twist/genética , Anomalías Múltiples/patología , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Inmunoprecipitación de Cromatina , Exoma/genética , Anomalías del Ojo/patología , Enfermedades de los Párpados/patología , Células HeLa , Hirsutismo/patología , Humanos , Hipertelorismo/patología , Hipertricosis/patología , Macrostomía/patología , Microscopía Electrónica , Datos de Secuencia Molecular , Mutación Missense/genética , Conformación Proteica , Proteínas Represoras/química , Análisis de Secuencia de ADN , Anomalías Cutáneas/patología , Proteína 1 Relacionada con Twist/química , Pez Cebra
17.
J Med Genet ; 54(2): 84-86, 2017 02.
Artículo en Inglés | MEDLINE | ID: mdl-27389779

RESUMEN

BACKGROUND: The causes of intellectual disability (ID) are diverse and de novo mutations are increasingly recognised to account for a significant proportion of ID. METHODS AND RESULTS: In this study, we performed whole exome sequencing on a large cohort of patients with ID or neurodevelopmental delay and identified four novel de novo predicted deleterious missense variants in HECW2 in six probands with ID/developmental delay and hypotonia. Other common features include seizures, strabismus, nystagmus, cortical visual impairment and dysmorphic facial features. HECW2 is an ubiquitin ligase that stabilises p73, a crucial mediator of neurodevelopment and neurogenesis. CONCLUSION: This study implicates pathogenic genetic variants in HECW2 as potential causes of neurodevelopmental disorders in humans.


Asunto(s)
Discapacidad Intelectual/genética , Hipotonía Muscular/genética , Trastornos del Neurodesarrollo/genética , Proteína Tumoral p73/genética , Ubiquitina-Proteína Ligasas/genética , Niño , Preescolar , Exoma/genética , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Discapacidad Intelectual/patología , Masculino , Hipotonía Muscular/patología , Mutación Missense/genética , Trastornos del Neurodesarrollo/patología
18.
Hum Mol Genet ; 24(11): 3050-7, 2015 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-25678555

RESUMEN

In mitochondria, carbamoyl-phosphate synthetase 1 activity produces carbamoyl phosphate for urea synthesis, and deficiency results in hyperammonemia. Cytoplasmic carbamoyl-phosphate synthetase 2, however, is part of a tri-functional enzyme encoded by CAD; no human disease has been attributed to this gene. The tri-functional enzyme contains carbamoyl-phosphate synthetase 2 (CPS2), aspartate transcarbamylase (ATCase) and dihydroorotase (DHOase) activities, which comprise the first three of six reactions required for de novo pyrimidine biosynthesis. Here we characterize an individual who is compound heterozygous for mutations in different domains of CAD. One mutation, c.1843-1G>A, results in an in-frame deletion of exon 13. The other, c.6071G>A, causes a missense mutation (p.Arg2024Gln) in a highly conserved residue that is essential for carbamoyl-phosphate binding. Metabolic flux studies showed impaired aspartate incorporation into RNA and DNA through the de novo synthesis pathway. In addition, CTP, UTP and nearly all UDP-activated sugars that serve as donors for glycosylation were decreased. Uridine supplementation rescued these abnormalities, suggesting a potential therapy for this new glycosylation disorder.


Asunto(s)
Aspartato Carbamoiltransferasa/genética , Carbamoil-Fosfato Sintasa (Glutamina-Hidrolizante)/genética , Dihidroorotasa/genética , Enfermedades Metabólicas/diagnóstico , Procesamiento Proteico-Postraduccional , Pirimidinas/biosíntesis , Animales , Secuencia de Bases , Células CHO , Preescolar , Cricetinae , Cricetulus , Análisis Mutacional de ADN , Estudios de Asociación Genética , Glicosilación , Heterocigoto , Humanos , Masculino , Enfermedades Metabólicas/genética , Mutación Missense , Eliminación de Secuencia
19.
Genet Med ; 19(12)2017 12.
Artículo en Inglés | MEDLINE | ID: mdl-28749475

RESUMEN

The purpose of this statement is to provide consensus-based recommendations for optimal management and care for patients with primary mitochondrial disease. This statement is intended for physicians who are engaged in the diagnosis and management of these patients. Working group members were appointed by the Mitochondrial Medicine Society. The panel included members with several different areas of expertise. The panel members utilized surveys and the Delphi method to reach consensus. We anticipate that this statement will need to be updated as the field continues to evolve. Consensus-based recommendations are provided for the routine care and management of patients with primary genetic mitochondrial disease.


Asunto(s)
Enfermedades Mitocondriales/diagnóstico , Enfermedades Mitocondriales/terapia , Nivel de Atención , Manejo de la Enfermedad , Humanos
20.
J Med Genet ; 53(3): 180-9, 2016 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-26668131

RESUMEN

BACKGROUND: Mutations in PLA2G6, which encodes the calcium-independent phospholipase A2 group VI, cause neurodegeneration and diffuse cortical Lewy body formation by a yet undefined mechanism. We assessed whether altered protein glycosylation due to abnormal Golgi morphology might be a factor in the pathology of this disease. METHODS: Three patients presented with PLA2G6-associated neurodegeneration (PLAN); two had infantile neuroaxonal dystrophy (INAD) and one had adult-onset dystonia-parkinsonism. We analysed protein N-linked and O-linked glycosylation in cerebrospinal fluid, plasma, urine, and cultured skin fibroblasts using high performance liquid chromatography (HPLC) and matrix-assisted laser desorption ionization--time of flight/mass spectrometry (MALDI-TOF/MS). We also assessed sialylation and Golgi morphology in cultured fibroblasts by immunofluorescence and performed rescue experiments using a lentiviral vector. RESULTS: The patients with INAD had PLA2G6 mutations NM_003560.2: c.[950G>T];[426-1077dup] and c.[1799G>A];[2221C>T] and the patient with dystonia-parkinsonism had PLA2G6 mutations NM_003560.2: c.[609G>A];[2222G>A]. All three patients had altered Golgi morphology and abnormalities of protein O-linked glycosylation and sialylation in cultured fibroblasts that were rescued by lentiviral overexpression of wild type PLA2G6. CONCLUSIONS: Our findings add altered Golgi morphology, O-linked glycosylation and sialylation defects to the phenotypical spectrum of PLAN; these pathways are essential for correct processing and distribution of proteins. Lewy body and Tau pathology, two neuropathological features of PLAN, could emerge from these defects. Therefore, Golgi morphology, O-linked glycosylation and sialylation may play a role in the pathogenesis of PLAN and perhaps other neurodegenerative disorders.


Asunto(s)
Trastornos Distónicos/metabolismo , Trastornos Distónicos/patología , Aparato de Golgi/ultraestructura , Fosfolipasas A2 Grupo VI/deficiencia , Distrofias Neuroaxonales/metabolismo , Distrofias Neuroaxonales/patología , Trastornos Parkinsonianos/metabolismo , Trastornos Parkinsonianos/patología , Adulto , Células Cultivadas , Trastornos Distónicos/genética , Femenino , Fibroblastos/metabolismo , Fibroblastos/ultraestructura , Glicosilación , Aparato de Golgi/metabolismo , Fosfolipasas A2 Grupo VI/genética , Fosfolipasas A2 Grupo VI/metabolismo , Humanos , Lactante , Masculino , Mutación , Distrofias Neuroaxonales/genética , Enfermedades Neurodegenerativas/genética , Enfermedades Neurodegenerativas/metabolismo , Enfermedades Neurodegenerativas/patología , Trastornos Parkinsonianos/genética , Sialiltransferasas/metabolismo
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