RESUMEN
We describe a case of an infant presenting with intractable diarrhea who subsequently developed dilated cardiomyopathy, for whom a diagnosis was not initially achieved despite extensive clinical testing, including panel-based genetic testing. Research-based whole-genome sequences of the proband and both parents were analyzed by the SAVANNA pipeline, a variant prioritization strategy integrating features of variants, genes, and phenotypes, which was implemented using publicly available tools. Although the intestinal morphological abnormalities characteristic of congenital tufting enteropathy (CTE) were not observed in the initial clinical gastrointestinal tract biopsies of the proband, an intronic variant, EPCAM c.556-14A>G, previously identified as pathogenic for CTE, was found in the homozygous state. A newborn cousin of the proband also presenting with intractable diarrhea was found to carry the same homozygous EPCAM variant, and clinical testing revealed intestinal tufting and loss of EPCAM staining. This variant, however, was considered nonexplanatory for the proband's dilated cardiomyopathy, which could be a sequela of the child's condition and/or related to other genetic variants, which include de novo mutations in the genes NEDD4L and GSK3A and a maternally inherited SCN5A variant. This study illustrates three ways in which genomic sequencing can aid in the diagnosis of clinically challenging patients: differential diagnosis despite atypical clinical presentation, distinguishing the possibilities of a syndromic condition versus multiple conditions, and generating hypotheses for novel contributory genes.
Asunto(s)
Diarrea Infantil/genética , Molécula de Adhesión Celular Epitelial/genética , Síndromes de Malabsorción/genética , Cardiomiopatía Dilatada/genética , Diagnóstico Diferencial , Diarrea/genética , Diarrea Infantil/diagnóstico , Molécula de Adhesión Celular Epitelial/metabolismo , Femenino , Genómica , Humanos , Lactante , Recién Nacido , Mucosa Intestinal/química , Intestinos/química , Intrones/genética , Síndromes de Malabsorción/diagnóstico , Mutación , Secuenciación Completa del GenomaRESUMEN
Polychlorinated biphenyls (PCBs) and their hydroxylated metabolites (OH-PCBs) are known to bind to transthyretin (TTR) in vitro, possibly explaining their bioaccumulation, rodent toxicity, and presumed human toxicity. Herein, we show that several OH-PCBs bind selectively to TTR in blood plasma; however, only one of the PCBs tested binds TTR in plasma. Some of the OH-PCBs displace thyroid hormone (T4) from TTR, rationalizing the toxicity observed in rodents, where TTR is the major T4 transporter. Thyroid binding globulin and albumin are the major T4 carriers in humans, making it unlikely that enough T4 could be displaced from TTR to be toxic. OH-PCBs are excellent TTR amyloidogenesis inhibitors in vitro because they bind to the TTR tetramer, imparting kinetic stability under amyloidogenic denaturing conditions. Four OH-PCB/TTR cocrystal structures provide further insight into inhibitor binding interactions.
Asunto(s)
Amiloide/antagonistas & inhibidores , Bifenilos Policlorados/farmacología , Prealbúmina/metabolismo , Amiloide/metabolismo , Animales , Cristalografía por Rayos X , Humanos , Ligandos , Modelos Moleculares , Estructura Molecular , Bifenilos Policlorados/química , Bifenilos Policlorados/toxicidad , Unión Proteica/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
Loeys-Dietz syndrome (LDS) is a connective tissue disorder that is characterized by a high risk for aneurysm and dissection throughout the arterial tree and phenotypically resembles Marfan syndrome. LDS is caused by heterozygous missense mutations in either TGF-ß receptor gene (TGFBR1 or TGFBR2), which are predicted to result in diminished TGF-ß signaling; however, aortic surgical samples from patients show evidence of paradoxically increased TGF-ß signaling. We generated 2 knockin mouse strains with LDS mutations in either Tgfbr1 or Tgfbr2 and a transgenic mouse overexpressing mutant Tgfbr2. Knockin and transgenic mice, but not haploinsufficient animals, recapitulated the LDS phenotype. While heterozygous mutant cells had diminished signaling in response to exogenous TGF-ß in vitro, they maintained normal levels of Smad2 phosphorylation under steady-state culture conditions, suggesting a chronic compensation. Analysis of TGF-ß signaling in the aortic wall in vivo revealed progressive upregulation of Smad2 phosphorylation and TGF-ß target gene output, which paralleled worsening of aneurysm pathology and coincided with upregulation of TGF-ß1 ligand expression. Importantly, suppression of Smad2 phosphorylation and TGF-ß1 expression correlated with the therapeutic efficacy of the angiotensin II type 1 receptor antagonist losartan. Together, these data suggest that increased TGF-ß signaling contributes to postnatal aneurysm progression in LDS.
Asunto(s)
Angiotensina II/fisiología , Aneurisma de la Aorta/metabolismo , Síndrome de Loeys-Dietz/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Bloqueadores del Receptor Tipo 1 de Angiotensina II/uso terapéutico , Animales , Aorta/patología , Aneurisma de la Aorta/prevención & control , Células Cultivadas , Progresión de la Enfermedad , Femenino , Haploinsuficiencia , Humanos , Síndrome de Loeys-Dietz/tratamiento farmacológico , Síndrome de Loeys-Dietz/patología , Losartán/uso terapéutico , Ratones , Ratones de la Cepa 129 , Ratones Endogámicos C57BL , Ratones Transgénicos , Mutación Missense , Miocitos del Músculo Liso/metabolismo , Fenotipo , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Receptor Tipo I de Factor de Crecimiento Transformador beta , Receptor Tipo II de Factor de Crecimiento Transformador beta , Receptores de Factores de Crecimiento Transformadores beta/genética , Receptores de Factores de Crecimiento Transformadores beta/metabolismo , Transducción de Señal , Proteína Smad2/metabolismoRESUMEN
OBJECTIVES: Bicuspid aortic valve is the most common congenital cardiac abnormality, occurring in 1% to 2% of the population, and often associates with ascending aortic aneurysm. Based on familial studies, bicuspid aortic valve with aneurysm segregates in an autosomal dominant manner with incomplete penetrance. NOTCH1 mutations have been reported in 6 families with prominent valve calcification and dysfunction and low penetrance of aneurysm. We sought to determine the contribution of NOTCH1 mutations to the more common phenotype of highly penetrant aneurysms with low penetrance of bicuspid aortic valve and with rare valve calcification or dysfunction. METHODS: All exons and splice junctions of NOTCH1 were sequenced in probands from 13 affected families presenting with bicuspid aortic valve with ascending aortic aneurysm in the absence of valve calcification. In addition, mutation analysis was performed on a single individual with aneurysm and calcified tricuspid aortic valve. Sequences were aligned and compared with the reference genomic sequence. RESULTS: Corroborating previous studies, analysis of the single sporadic patient with calcified aortic valve in the presence of ascending aortic aneurysm revealed a novel heterozygous missense mutation in NOTCH1 resulting in a nonsynonymous amino acid substitution (p.T1090S, c.C3269G) of an evolutionarily conserved residue. This change was not observed in controls. In contrast, we did not identify any pathologic NOTCH1 mutations in the 13 families segregating noncalcified bicuspid aortic valve with highly penetrant aortic aneurysm. CONCLUSIONS: These data suggest that there are phenotypic differences that distinguish families with and without NOTCH1 mutations, indicating a genotype-phenotype correlation with potential implications for patient diagnosis, counseling, and management.
Asunto(s)
Aneurisma de la Aorta/complicaciones , Aneurisma de la Aorta/genética , Estudios de Asociación Genética , Mutación , Receptor Notch1/genética , Adolescente , Adulto , Válvula Aórtica/anomalías , Enfermedad de la Válvula Aórtica Bicúspide , Niño , Femenino , Enfermedades de las Válvulas Cardíacas , Humanos , Masculino , Linaje , Adulto JovenRESUMEN
The autosomal dominant inheritance of bicommissural aortic valve (BAV) (Online Mendelian Inheritance in Man #109730) in some families is well-documented; however, the inheritance of BAV with thoracic aortic aneurysm (TAA) is less clear. Whether the aneurysm is secondary to hemodynamic perturbation related to the valve abnormality or a primary manifestation of the disorder remains controversial. Guidelines are needed regarding the follow-up and treatment of these patients and their families. Thirteen families with at least one individual with TAA and BAV (BAV/TAA) were evaluated prospectively by standard echocardiographic methods or clinical history. Affected status was determined by the presence of BAV or TAA or a history of dissection, rupture, or surgical repair. Six of 13 families had at least two family members with both BAV and TAA, often in successive generations. Informatively, all 13 families had at least one family member with TAA in the absence of BAV. Thirty-five percent (39/110) of family members had BAV/TAA or TAA, and the majority of families (11/13) had maximal dilatation above the sinotubular junction (STJ). Vascular dissection or rupture occurred in seven of 13 families and in individuals with structurally normal aortic valves. Two families had non-manifesting, obligate carriers. Three families have members with other left heart outflow tract anomalies. This study confirms autosomal dominant inheritance with incomplete penetrance for BAV/TAA in these families. Furthermore, our data suggest that the component features, BAV and TAA, are independent manifestations of a single gene defect. To avoid the risk of early death, it is essential that all first-degree relatives receive echocardiographic follow-up at regular intervals regardless of the presence or absence of a BAV. This assessment must include imaging of the aortic region above the STJ.
Asunto(s)
Aneurisma de la Aorta Torácica/genética , Válvula Aórtica/anomalías , Enfermedades de las Válvulas Cardíacas/genética , Aneurisma de la Aorta Torácica/etiología , Aneurisma de la Aorta Torácica/terapia , Femenino , Genes Dominantes , Enfermedades de las Válvulas Cardíacas/etiología , Enfermedades de las Válvulas Cardíacas/terapia , Humanos , Masculino , Linaje , Estudios Prospectivos , Proteínas Serina-Treonina Quinasas/genética , Receptor Tipo I de Factor de Crecimiento Transformador beta , Receptor Tipo II de Factor de Crecimiento Transformador beta , Receptores de Factores de Crecimiento Transformadores beta/genéticaRESUMEN
Genomic imprinting is theorized to exist in all placental mammals and some marsupials; however, extensive comparative analysis of animals aside from humans and mice remains incomplete. Here we report conservation of genomic imprinting in the bovine at the X chromosome inactivation-specific transcript (XIST), insulin-like growth factor 2 (IGF2), and gene trap locus 2 (GTL2) loci. Coding single nucleotide polymorphisms (SNPs) between Bos gaurus and Bos taurus were detected at the XIST, IGF2, and GTL2 loci, which have previously been identified as imprinted in either humans, mice, or sheep. Expression patterns of parental alleles in F1 hybrids indicated preferential paternal expression at the XIST locus solely in the chorion of females, whereas analysis of the IGF2 and GTL2 loci indicated preferential paternal and maternal expression of alleles, respectively, in both fetal and placental tissues. Comparative sequence analysis of the XIST locus and adjacent regions suggests that repression of the maternal allele in the bovine is controlled by a different mechanism than in mice, further reinforcing the importance of comparative analysis of imprinting.