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1.
Am J Hum Genet ; 108(9): 1710-1724, 2021 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-34450031

RESUMO

Coatomer complexes function in the sorting and trafficking of proteins between subcellular organelles. Pathogenic variants in coatomer subunits or associated factors have been reported in multi-systemic disorders, i.e., coatopathies, that can affect the skeletal and central nervous systems. We have identified loss-of-function variants in COPB2, a component of the coatomer complex I (COPI), in individuals presenting with osteoporosis, fractures, and developmental delay of variable severity. Electron microscopy of COPB2-deficient subjects' fibroblasts showed dilated endoplasmic reticulum (ER) with granular material, prominent rough ER, and vacuoles, consistent with an intracellular trafficking defect. We studied the effect of COPB2 deficiency on collagen trafficking because of the critical role of collagen secretion in bone biology. COPB2 siRNA-treated fibroblasts showed delayed collagen secretion with retention of type I collagen in the ER and Golgi and altered distribution of Golgi markers. copb2-null zebrafish embryos showed retention of type II collagen, disorganization of the ER and Golgi, and early larval lethality. Copb2+/- mice exhibited low bone mass, and consistent with the findings in human cells and zebrafish, studies in Copb2+/- mouse fibroblasts suggest ER stress and a Golgi defect. Interestingly, ascorbic acid treatment partially rescued the zebrafish developmental phenotype and the cellular phenotype in Copb2+/- mouse fibroblasts. This work identifies a form of coatopathy due to COPB2 haploinsufficiency, explores a potential therapeutic approach for this disorder, and highlights the role of the COPI complex as a regulator of skeletal homeostasis.


Assuntos
Osso e Ossos/metabolismo , Complexo I de Proteína do Envoltório/genética , Proteína Coatomer/genética , Deficiências do Desenvolvimento/genética , Deficiência Intelectual/genética , Osteoporose/genética , Animais , Ácido Ascórbico/farmacologia , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/patologia , Encéfalo/diagnóstico por imagem , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Criança , Pré-Escolar , Complexo I de Proteína do Envoltório/deficiência , Proteína Coatomer/química , Proteína Coatomer/deficiência , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Deficiências do Desenvolvimento/diagnóstico por imagem , Deficiências do Desenvolvimento/metabolismo , Deficiências do Desenvolvimento/patologia , Embrião não Mamífero , Retículo Endoplasmático/efeitos dos fármacos , Retículo Endoplasmático/metabolismo , Retículo Endoplasmático/patologia , Feminino , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/patologia , Regulação da Expressão Gênica no Desenvolvimento , Complexo de Golgi , Haploinsuficiência , Humanos , Deficiência Intelectual/diagnóstico por imagem , Deficiência Intelectual/metabolismo , Deficiência Intelectual/patologia , Masculino , Camundongos , Osteoporose/tratamento farmacológico , Osteoporose/metabolismo , Osteoporose/patologia , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Índice de Gravidade de Doença , Peixe-Zebra
2.
Am J Med Genet A ; 191(12): 2825-2830, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37548074

RESUMO

Subdural hemorrhages (SDHs) in children are most often observed in abusive head trauma (AHT), a distinct form of traumatic brain injury, but they may occur in other conditions as well, typically with clear signs and symptoms of an alternative diagnosis. We present a case of an infant whose SDH initially raised the question of AHT, but multidisciplinary evaluation identified multiple abnormalities, including rash, macrocephaly, growth failure, and elevated inflammatory markers, which were all atypical for trauma. These, along with significant cerebral atrophy, ventriculomegaly, and an absence of other injuries, raised concerns for a genetic disorder, prompting genetic consultation. Clinical trio exome sequencing identified a de novo likely pathogenic variant in NLRP3, which is associated with chronic infantile neurological, cutaneous, and articular (CINCA) syndrome, also known as neonatal-onset multisystem inflammatory disease (NOMID). He was successfully treated with interleukin-1 blockade, highlighting the importance of prompt treatment in CINCA/NOMID patients. This case also illustrates how atraumatic cases of SDH can be readily distinguished from AHT with multidisciplinary collaboration and careful consideration of the clinical history and exam findings.


Assuntos
Maus-Tratos Infantis , Síndromes Periódicas Associadas à Criopirina , Exantema , Megalencefalia , Humanos , Lactente , Recém-Nascido , Masculino , Síndromes Periódicas Associadas à Criopirina/tratamento farmacológico , Síndromes Periódicas Associadas à Criopirina/genética , Síndromes Periódicas Associadas à Criopirina/patologia , Hematoma Subdural , Megalencefalia/diagnóstico , Megalencefalia/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética
3.
Kidney Int ; 101(5): 1039-1053, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35227688

RESUMO

Congenital anomalies of the kidney and urinary tract (CAKUT) represent the most common cause of chronic kidney failure in children. Despite growing knowledge of the genetic causes of CAKUT, the majority of cases remain etiologically unsolved. Genetic alterations in roundabout guidance receptor 1 (ROBO1) have been associated with neuronal and cardiac developmental defects in living individuals. Although Slit-Robo signaling is pivotal for kidney development, diagnostic ROBO1 variants have not been reported in viable CAKUT to date. By next-generation-sequencing methods, we identified six unrelated individuals and two non-viable fetuses with biallelic truncating or combined missense and truncating variants in ROBO1. Kidney and genitourinary manifestation included unilateral or bilateral kidney agenesis, vesicoureteral junction obstruction, vesicoureteral reflux, posterior urethral valve, genital malformation, and increased kidney echogenicity. Further clinical characteristics were remarkably heterogeneous, including neurodevelopmental defects, intellectual impairment, cerebral malformations, eye anomalies, and cardiac defects. By in silico analysis, we determined the functional significance of identified missense variants and observed absence of kidney ROBO1 expression in both human and murine mutant tissues. While its expression in multiple tissues may explain heterogeneous organ involvement, variability of the kidney disease suggests gene dosage effects due to a combination of null alleles with mild hypomorphic alleles. Thus, comprehensive genetic analysis in CAKUT should include ROBO1 as a new cause of recessively inherited disease. Hence, in patients with already established ROBO1-associated cardiac or neuronal disorders, screening for kidney involvement is indicated.


Assuntos
Proteínas do Tecido Nervoso/genética , Receptores Imunológicos/genética , Sistema Urinário , Anormalidades Urogenitais , Refluxo Vesicoureteral , Animais , Criança , Feminino , Humanos , Rim/patologia , Masculino , Camundongos , Sistema Urinário/patologia , Anormalidades Urogenitais/diagnóstico , Anormalidades Urogenitais/genética , Refluxo Vesicoureteral/diagnóstico , Proteínas Roundabout
4.
Genet Med ; 21(9): 2059-2069, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-30923367

RESUMO

PURPOSE: To investigate the effect of different DEAF1 variants on the phenotype of patients with autosomal dominant and recessive inheritance patterns and on DEAF1 activity in vitro. METHODS: We assembled a cohort of 23 patients with de novo and biallelic DEAF1 variants, described the genotype-phenotype correlation, and investigated the differential effect of de novo and recessive variants on transcription assays using DEAF1 and Eif4g3 promoter luciferase constructs. RESULTS: The proportion of the most prevalent phenotypic features, including intellectual disability, speech delay, motor delay, autism, sleep disturbances, and a high pain threshold, were not significantly different in patients with biallelic and pathogenic de novo DEAF1 variants. However, microcephaly was exclusively observed in patients with recessive variants (p < 0.0001). CONCLUSION: We propose that different variants in the DEAF1 gene result in a phenotypic spectrum centered around neurodevelopmental delay. While a pathogenic de novo dominant variant would also incapacitate the product of the wild-type allele and result in a dominant-negative effect, a combination of two recessive variants would result in a partial loss of function. Because the clinical picture can be nonspecific, detailed phenotype information, segregation, and functional analysis are fundamental to determine the pathogenicity of novel variants and to improve the care of these patients.


Assuntos
Proteínas de Ligação a DNA/genética , Deficiências do Desenvolvimento/genética , Deficiência Intelectual/genética , Microcefalia/genética , Fatores de Transcrição/genética , Adolescente , Adulto , Alelos , Transtorno Autístico/genética , Transtorno Autístico/patologia , Criança , Pré-Escolar , Deficiências do Desenvolvimento/patologia , Exoma/genética , Feminino , Estudos de Associação Genética , Humanos , Deficiência Intelectual/patologia , Transtornos do Desenvolvimento da Linguagem/genética , Transtornos do Desenvolvimento da Linguagem/patologia , Masculino , Microcefalia/patologia , Mutação de Sentido Incorreto/genética , Adulto Jovem
5.
Clin Dysmorphol ; 26(4): 252-255, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28872565

RESUMO

In the field of dysmorphology, achondroplasia is a well-known disorder. Sinus pericranii (SP), however, is not. The latter condition is a rare vascular malformation characterized by abnormal connections between the intracranial and the extracranial venous drainage pathways. The etiology of SP remains unclear, and yet, these defects can be present at birth, develop spontaneously later, or evolve following head trauma. Here, we report on a 2-year-old male with achondroplasia, SP, and craniocervical junction stenosis. The latter two defects required surgical correction. SP is an underappreciated malformation that we propose may be induced by increased intracranial pressure. This case appears to be the first report of this condition in achondroplasia.


Assuntos
Acondroplasia/complicações , Seio Pericrânio/complicações , Acondroplasia/diagnóstico por imagem , Acondroplasia/cirurgia , Pré-Escolar , Humanos , Lactente , Imageamento por Ressonância Magnética , Masculino , Monitorização Intraoperatória , Seio Pericrânio/diagnóstico por imagem , Seio Pericrânio/cirurgia
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