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1.
Am J Hum Genet ; 109(10): 1932-1943, 2022 10 06.
Artículo en Inglés | MEDLINE | ID: mdl-36206744

RESUMEN

Proteins containing the FERM (four-point-one, ezrin, radixin, and moesin) domain link the plasma membrane with cytoskeletal structures at specific cellular locations and have been implicated in the localization of cell-membrane-associated proteins and/or phosphoinositides. FERM domain-containing protein 5 (FRMD5) localizes at cell adherens junctions and stabilizes cell-cell contacts. To date, variants in FRMD5 have not been associated with a Mendelian disease in OMIM. Here, we describe eight probands with rare heterozygous missense variants in FRMD5 who present with developmental delay, intellectual disability, ataxia, seizures, and abnormalities of eye movement. The variants are de novo in all for whom parental testing was available (six out of eight probands), and human genetic datasets suggest that FRMD5 is intolerant to loss of function (LoF). We found that the fly ortholog of FRMD5, CG5022 (dFrmd), is expressed in the larval and adult central nervous systems where it is present in neurons but not in glia. dFrmd LoF mutant flies are viable but are extremely sensitive to heat shock, which induces severe seizures. The mutants also exhibit defective responses to light. The human FRMD5 reference (Ref) cDNA rescues the fly dFrmd LoF phenotypes. In contrast, all the FRMD5 variants tested in this study (c.340T>C, c.1051A>G, c.1053C>G, c.1054T>C, c.1045A>C, and c.1637A>G) behave as partial LoF variants. In addition, our results indicate that two variants that were tested have dominant-negative effects. In summary, the evidence supports that the observed variants in FRMD5 cause neurological symptoms in humans.


Asunto(s)
Discapacidad Intelectual , Animales , Ataxia/genética , ADN Complementario , Discapacidades del Desarrollo/genética , Movimientos Oculares , Humanos , Discapacidad Intelectual/genética , Proteínas de la Membrana , Fosfatidilinositoles , Convulsiones , Proteínas Supresoras de Tumor/genética
2.
Am J Hum Genet ; 107(1): 164-172, 2020 07 02.
Artículo en Inglés | MEDLINE | ID: mdl-32553196

RESUMEN

CNOT1 is a member of the CCR4-NOT complex, which is a master regulator, orchestrating gene expression, RNA deadenylation, and protein ubiquitination. We report on 39 individuals with heterozygous de novo CNOT1 variants, including missense, splice site, and nonsense variants, who present with a clinical spectrum of intellectual disability, motor delay, speech delay, seizures, hypotonia, and behavioral problems. To link CNOT1 dysfunction to the neurodevelopmental phenotype observed, we generated variant-specific Drosophila models, which showed learning and memory defects upon CNOT1 knockdown. Introduction of human wild-type CNOT1 was able to rescue this phenotype, whereas mutants could not or only partially, supporting our hypothesis that CNOT1 impairment results in neurodevelopmental delay. Furthermore, the genetic interaction with autism-spectrum genes, such as ASH1L, DYRK1A, MED13, and SHANK3, was impaired in our Drosophila models. Molecular characterization of CNOT1 variants revealed normal CNOT1 expression levels, with both mutant and wild-type alleles expressed at similar levels. Analysis of protein-protein interactions with other members indicated that the CCR4-NOT complex remained intact. An integrated omics approach of patient-derived genomics and transcriptomics data suggested only minimal effects on endonucleolytic nonsense-mediated mRNA decay components, suggesting that de novo CNOT1 variants are likely haploinsufficient hypomorph or neomorph, rather than dominant negative. In summary, we provide strong evidence that de novo CNOT1 variants cause neurodevelopmental delay with a wide range of additional co-morbidities. Whereas the underlying pathophysiological mechanism warrants further analysis, our data demonstrate an essential and central role of the CCR4-NOT complex in human brain development.


Asunto(s)
Discapacidades del Desarrollo/genética , Expresión Génica/genética , Trastornos del Neurodesarrollo/genética , Miembro 2 del Grupo A de la Subfamilia 4 de Receptores Nucleares/genética , ARN/genética , Receptores CCR4/genética , Factores de Transcripción/genética , Alelos , Femenino , Variación Genética/genética , Haploinsuficiencia/genética , Heterocigoto , Humanos , Masculino , Malformaciones del Sistema Nervioso/genética , Fenotipo , Estabilidad Proteica
3.
Genet Med ; 17(7): 561-8, 2015 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-25503497

RESUMEN

PURPOSE: The aim of this study was to examine predictors of ammonia exposure and hyperammonemic crises in patients with urea cycle disorders. METHODS: The relationships between fasting ammonia, daily ammonia exposure, and hyperammonemic crises were analyzed in >100 patients with urea cycle disorders. RESULTS: Fasting ammonia correlated strongly with daily ammonia exposure (r = 0.764; P < 0.001). For patients with fasting ammonia concentrations <0.5 upper limit of normal (ULN), 0.5 to <1.0 ULN, and ≥1.0 ULN, the probability of a normal average daily ammonia value was 87, 60, and 39%, respectively, and 10.3, 14.1, and 37.0% of these patients, respectively, experienced ≥1 hyperammonemic crisis over 12 months. Time to first hyperammonemic crisis was shorter (P = 0.008) and relative risk (4.5×; P = 0.011) and rate (~5×, P = 0.006) of hyperammonemic crises were higher in patients with fasting ammonia ≥1.0 ULN vs. <0.5ULN; relative risk was even greater (20×; P = 0.009) in patients ≥6 years old. A 10- or 25-µmol/l increase in ammonia exposure increased the relative risk of a hyperammonemic crisis by 50 and >200% (P < 0.0001), respectively. The relationship between ammonia and hyperammonemic crisis risk seemed to be independent of treatment, age, urea cycle disorder subtype, dietary protein intake, or blood urea nitrogen. Fasting glutamine correlated weakly with daily ammonia exposure assessed as 24-hour area under the curve and was not a significant predictor of hyperammonemic crisis. CONCLUSION: Fasting ammonia correlates strongly and positively with daily ammonia exposure and with the risk and rate of hyperammonemic crises, suggesting that patients with urea cycle disorder may benefit from tight ammonia control.


Asunto(s)
Amoníaco/sangre , Glutamina/sangre , Hiperamonemia/sangre , Trastornos Innatos del Ciclo de la Urea/sangre , Adolescente , Adulto , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Adulto Joven
4.
Mol Genet Metab ; 116(1-2): 29-34, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26296711

RESUMEN

BACKGROUND: Health care outcomes have been increasingly assessed through health-related quality of life (HRQoL) measures. While the introduction of nitrogen-scavenging medications has improved survival in patients with urea cycle disorders (UCDs), they are often associated with side effects that may affect patient compliance and outcomes. METHODS: Symptoms commonly associated with nitrogen-scavenging medications were evaluated in 100 adult and pediatric participants using a non-validated UCD-specific questionnaire. Patients or their caregivers responded to a pre-defined list of symptoms known to be associated with the use of these medications. Responses were collected at baseline (while patients were receiving sodium phenylbutyrate [NaPBA]) and during treatment with glycerol phenylbutyrate (GPB). RESULTS: After 3 months of GPB dosing, there were significant reductions in the proportion of patients with treatment-associated symptoms (69% vs. 46%; p<0.0001), the number of symptoms per patient (2.5 vs. 1.1; p<0.0001), and frequency of the more commonly reported individual symptoms such as body odor, abdominal pain, nausea, burning sensation in mouth, vomiting, and heartburn (p<0.05). The reduction in symptoms was observed in both pediatric and adult patients. The presence or absence of symptoms or change in severity did not correlate with plasma ammonia levels or NaPBA dose. CONCLUSIONS: The reduction in symptoms following 3 months of open-label GPB dosing was similar in pediatric and adult patients and may be related to chemical structure and intrinsic characteristics of the product rather than its effect on ammonia control.


Asunto(s)
Glicerol/análogos & derivados , Fenilbutiratos/efectos adversos , Calidad de Vida , Autoinforme , Trastornos Innatos del Ciclo de la Urea/tratamiento farmacológico , Adolescente , Adulto , Anciano , Amoníaco/sangre , Antineoplásicos/uso terapéutico , Niño , Preescolar , Femenino , Glicerol/efectos adversos , Glicerol/química , Glicerol/uso terapéutico , Humanos , Lactante , Masculino , Persona de Mediana Edad , Fenilbutiratos/química , Fenilbutiratos/uso terapéutico , Encuestas y Cuestionarios , Trastornos Innatos del Ciclo de la Urea/sangre , Trastornos Innatos del Ciclo de la Urea/psicología , Adulto Joven
5.
Hepatology ; 57(6): 2171-9, 2013 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-22961727

RESUMEN

UNLABELLED: Glycerol phenylbutyrate is under development for treatment of urea cycle disorders (UCDs), rare inherited metabolic disorders manifested by hyperammonemia and neurological impairment. We report the results of a pivotal Phase 3, randomized, double-blind, crossover trial comparing ammonia control, assessed as 24-hour area under the curve (NH3 -AUC0-24hr ), and pharmacokinetics during treatment with glycerol phenylbutyrate versus sodium phenylbutyrate (NaPBA) in adult UCD patients and the combined results of four studies involving short- and long-term glycerol phenylbutyrate treatment of UCD patients ages 6 and above. Glycerol phenylbutyrate was noninferior to NaPBA with respect to ammonia control in the pivotal study, with mean (standard deviation, SD) NH3 -AUC0-24hr of 866 (661) versus 977 (865) µmol·h/L for glycerol phenylbutyrate and NaPBA, respectively. Among 65 adult and pediatric patients completing three similarly designed short-term comparisons of glycerol phenylbutyrate versus NaPBA, NH3 -AUC0-24hr was directionally lower on glycerol phenylbutyrate in each study, similar among all subgroups, and significantly lower (P < 0.05) in the pooled analysis, as was plasma glutamine. The 24-hour ammonia profiles were consistent with the slow-release behavior of glycerol phenylbutyrate and better overnight ammonia control. During 12 months of open-label glycerol phenylbutyrate treatment, average ammonia was normal in adult and pediatric patients and executive function among pediatric patients, including behavioral regulation, goal setting, planning, and self-monitoring, was significantly improved. CONCLUSION: Glycerol phenylbutyrate exhibits favorable pharmacokinetics and ammonia control relative to NaPBA in UCD patients, and long-term glycerol phenylbutyrate treatment in pediatric UCD patients was associated with improved executive function (ClinicalTrials.gov NCT00551200, NCT00947544, NCT00992459, NCT00947297). (HEPATOLOGY 2012).


Asunto(s)
Amoníaco/sangre , Glicerol/análogos & derivados , Fenilbutiratos/uso terapéutico , Trastornos Innatos del Ciclo de la Urea/tratamiento farmacológico , Adolescente , Adulto , Niño , Estudios Cruzados , Método Doble Ciego , Femenino , Glutamina/sangre , Glicerol/uso terapéutico , Humanos , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Trastornos Innatos del Ciclo de la Urea/sangre , Adulto Joven
6.
Hum Mutat ; 34(3): 446-52, 2013 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-23281071

RESUMEN

Mitochondrial complex III (CIII) deficiency is a relatively rare disease with high clinical and genetic heterogeneity. CIII comprises 11 subunits encoded by one mitochondrial and 10 nuclear genes. Abnormalities of the nuclear genes such as BCS1L and TTC19 encoding mitochondrial assembly factors are well known, but an explanation of the majority of CIII deficiency remains elusive. Here, we report three patients from a consanguineous Mexican family presenting with neonatal onset of hypoglycemia, lactic acidosis, ketosis, and hyperammonemia. We found a homozygous missense mutation in UQCRC2 that encodes mitochondrial ubiquinol-cytochrome c reductase core protein II by whole-exome sequencing combined with linkage analysis. On the basis of structural modeling, the mutation (p.Arg183Trp) was predicted to destabilize the hydrophobic core at the subunit interface of the core protein II homodimer. In vitro studies using fibroblasts from the index patient clearly indicated CIII deficiency, as well as impaired assembly of the supercomplex formed from complexes I, III, and IV. This is the first described human disease caused by a core protein abnormality in mitochondrial CIII.


Asunto(s)
Complejo III de Transporte de Electrones/genética , Homocigoto , Enfermedades Mitocondriales/diagnóstico , Enfermedades Mitocondriales/genética , Mutación Missense , ATPasas Asociadas con Actividades Celulares Diversas , Acidosis Láctica/genética , Adulto , Western Blotting , Complejo III de Transporte de Electrones/deficiencia , Exoma , Femenino , Ligamiento Genético , Humanos , Hiperamonemia/genética , Hipoglucemia/genética , Cetosis/genética , Masculino , Proteínas de la Membrana/genética , Mitocondrias/genética , Proteínas Mitocondriales/genética , Linaje , Conformación Proteica , Análisis de Secuencia de ADN
7.
Mol Genet Metab Rep ; 6: 34-40, 2016 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-27014577

RESUMEN

BACKGROUND: Little prospectively collected data are available comparing the dietary intake of urea cycle disorder (UCD) patients to UCD treatment guidelines or to healthy individuals. OBJECTIVE: To examine the protein and calorie intakes of UCD subjects who participated in clinical trials of glycerol phenylbutyrate (GPB) and compare these data to published UCD dietary guidelines and nutritional surveys. DESIGN: Dietary data were recorded for 45 adult and 49 pediatric UCD subjects in metabolic control during participation in clinical trials of GPB. Protein and calorie intakes were compared to UCD treatment guidelines, average nutrient intakes of a healthy US population based on the National Health and Nutrition Examination Survey (NHANES) and Recommended Daily Allowances (RDA). RESULTS: In adults, mean protein intake was higher than UCD recommendations but lower than RDA and NHANES values, while calorie intake was lower than UCD recommendations, RDA and NHANES. In pediatric subjects, prescribed protein intake was higher than UCD guidelines, similar to RDA, and lower than NHANES data for all age groups, while calorie intake was at the lower end of the recommended UCD range and close to RDA and NHANES data. In pediatric subjects height, weight, and body mass index (BMI) Z-scores were within normal range (- 2 to 2). CONCLUSIONS: Pediatric patients treated with phenylbutyrate derivatives exhibited normal height and weight. Protein and calorie intakes in adult and pediatric UCD subjects differed from UCD dietary guidelines, suggesting that these guidelines may need to be reconsidered.

8.
Eur J Hum Genet ; 23(1): 61-6, 2015 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-24713661

RESUMEN

Whole-genome oligonucleotide single-nucleotide polymorphism (oligo-SNP) arrays enable simultaneous interrogation of copy number variations (CNVs), copy neutral regions of homozygosity (ROH) and uniparental disomy (UPD). Structural variation in the human genome contributes significantly to genetic variation, and often has deleterious effects leading to disease causation. Co-occurrence of CNV and regions of allelic homozygosity in tandem involving the same chromosomal arm are extremely rare. Replication-based mechanisms such as microhomology-mediated break-induced replication (MMBIR) are recent models predicted to induce structural rearrangements and gene dosage aberrations; however, supportive evidence in humans for one-ended DNA break repair coupled with MMBIR giving rise to interstitial copy number gains and distal loss of heterozygosity has not been documented. We report on the identification and characterization of two cases with interstitial triplication followed by uniparental isodisomy (isoUPD) for remainder of the chromosomal arm. Case 1 has a triplication at 9q21.11-q21.33 and segmental paternal isoUPD for 9q21.33-qter, and presented with citrullinemia with a homozygous mutation in the argininosuccinate synthetase gene (ASS1 at 9q34.1). Case 2 has a triplication at 22q12.1-q12.2 and segmental maternal isoUPD 22q12.2-qter, and presented with hearing loss, mild dysmorphic features and bilateral iris coloboma. Interstitial triplication coupled with distal segmental isoUPD is a novel finding that provides human evidence for one-ended DNA break and replication-mediated repair. Both copy number gains and isoUPD may contribute to the phenotype. Significantly, these cases represent the first detailed genomic analysis that provides support for a MMBIR mechanism inducing copy number gains and segmental isoUPD in tandem.


Asunto(s)
Disomía Uniparental/diagnóstico , Disomía Uniparental/genética , Preescolar , Bandeo Cromosómico , Cromosomas Humanos Par 22 , Cromosomas Humanos Par 9 , Consanguinidad , Roturas del ADN , Variaciones en el Número de Copia de ADN , Femenino , Reordenamiento Génico , Genotipo , Recombinación Homóloga , Humanos , Hibridación Fluorescente in Situ , Modelos Genéticos , Polimorfismo de Nucleótido Simple
10.
Respir Physiol Neurobiol ; 179(2-3): 137-41, 2011 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-21802532

RESUMEN

Nasal morphology plays an important functional role in the maintenance of upper airway health. Identification of functional regions, based on morphological attributes, assists in correlating location to primary purpose. The effects of morphological variation on heat and water mass transport in congested and patent nasal airways were investigated by examining nasal cross-sectional MRI images from 8 healthy subjects. This research confirms the previous identification of functional air-conditioning regions within the nose. The first is the anterior region where the morphology prevents over-stressing of tissue heat and fluid supply near the nares. The second is the mid region where low flow velocity favours olfaction and particle deposition. The third is the posterior region which demonstrates an increase in heat and water mass flux coefficients to compensate for rising air humidity and temperature. Factors identified within the congested airway that favour enhanced mucocillary clearance were also identified.


Asunto(s)
Cavidad Nasal/anatomía & histología , Cavidad Nasal/fisiología , Adulto , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Adulto Joven
11.
Am J Rhinol ; 20(5): 425-9, 2006.
Artículo en Inglés | MEDLINE | ID: mdl-17063731

RESUMEN

BACKGROUND: The role of nasal levels of nitric oxide (nNO) as noninvasive marker of inflammation and as an outcome variable in allergic upper respiratory tract disease has not been defined. Our aim is to determine in patients with perennial allergic rhinitis (i) whether nNO is elevated, (ii) whether increased nNO is correlated with upper respiratory tract symptoms (discrimination), and (iii) whether changes in symptom scores are associated with changes in nNO levels (responsiveness). METHODS: Subjects (n = 38) with perennial rhinitis were studied weekly for 3 weeks. At each visit they completed a validated symptom questionnaire and had expired NO and nNO measured. RESULTS: Nasal NO levels were higher in those allergic to house-dust mite and cat. Nasal NO levels in subjects with perennial rhinitis were not elevated compared with non-atopic asymptomatic subjects. The intra-week reproducibility of nNO measurements was poor. There was no relationship between the symptom scores and nasal NO levels (discrimination). When analysis was confined to nasal symptoms, a weak but negative correlation was identified. Changes in symptom scores from week to week were not correlated with changes in nNO levels (responsiveness). CONCLUSIONS: Nasal NO levels were not elevated in subjects with perennial rhinitis, and nNO levels were neither discriminatory nor responsive. The measurement of nNO therefore appears not to be a useful marker of disease activity in subjects with allergic rhinitis.


Asunto(s)
Asma/metabolismo , Mucosa Nasal/metabolismo , Óxido Nítrico/análisis , Trastornos Respiratorios/metabolismo , Rinitis Alérgica Perenne/metabolismo , Rinitis Alérgica Estacional/metabolismo , Adulto , Alérgenos/inmunología , Asma/inmunología , Pruebas Respiratorias , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pruebas de Provocación Nasal , Trastornos Respiratorios/fisiopatología , Rinitis Alérgica Perenne/inmunología , Rinitis Alérgica Perenne/fisiopatología , Rinitis Alérgica Estacional/inmunología , Rinitis Alérgica Estacional/fisiopatología , Pruebas Cutáneas , Factores de Tiempo
12.
Am J Med Genet A ; 121A(3): 277-80, 2003 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-12923871

RESUMEN

Marker chromosomes originating from chromosome 15, often referred to as inv dup(15), is the most common marker chromosome found in humans. The large marker 15 that contains the Prader-Willi syndrome (PWS)/Angelman syndrome (AS) chromosome region is usually associated with an abnormal phenotype of moderate to severe mental retardation, seizures, poor motor coordination, behavioral problems, and mild dysmorphic features. We report here an infant boy with two copies of the large inv dup(15). A 10-day-old infant was found to have infantile spasms, microcephaly, hypotonia, and lethargy. Lymphocyte chromosome analysis revealed a 48,XY, +2mar karyotype. Fluorescence in situ hybridization with probes rRNA, D15Z4, D15S11, and GABRB3 demonstrated that both markers were chromosome 15 in origin and contained the Prader-Willi/Angelman syndrome chromosome region. Therefore, this patient is hexasomic for the PWS/AS region. The phenotype of this patient does not appear to be significantly more severe than patients with one copy of the large inv dup(15) at birth, however, follow-up evaluation of the patient at 21 months of age shows that this patient has frequent and severe seizure activity, severe bilateral hearing loss, and cortical blindness.


Asunto(s)
Síndrome de Angelman/genética , Inversión Cromosómica , Cromosomas Humanos Par 15/genética , Síndrome de Prader-Willi/genética , Adulto , Síndrome de Angelman/diagnóstico , Trastornos de los Cromosomas , Femenino , Humanos , Hibridación Fluorescente in Situ , Lactante , Recién Nacido , Cariotipificación , Masculino , Fenotipo , Síndrome de Prader-Willi/diagnóstico , Embarazo
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