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1.
Am J Med Genet A ; 179(9): 1783-1790, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31294511

RESUMO

Rare individuals with 20p11.2 proximal deletions have been previously reported, with a variable phenotype that includes heterotaxy, biliary atresia, midline brain defects associated with panhypopituitarism, intellectual disability, scoliosis, and seizures. Deletions have ranged in size from 277 kb to 11.96 Mb. We describe a newborn with a de novo 2.7 Mb deletion of 20p11.22p11.21 that partially overlaps previously reported deletions and encompasses FOXA2. Her clinical findings further expand the 20p11.2 deletion phenotype to include severe midline cranial and intracranial defects such as aqueductal stenosis with hydrocephalus, mesencephalosynapsis with diencephalic-mesencephalic junction dysplasia, and pyriform aperture stenosis. We also report one individual with a missense variant in FOXA2 who had abnormal glucose homeostasis, panhypopituitarism, and endodermal organ dysfunction. Together, these findings support the critical role of FOXA2 in panhypopituitarism and midline defects.

2.
Am J Med Genet A ; 179(5): 842-845, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30828993

RESUMO

We describe a neonate with severe respiratory failure due to acinar dysplasia found by rapid exome sequencing (rES), to have a deletion containing the TBX4 gene. rES can affect patient management in the intensive care unit and should be considered in concert with lung biopsy in neonates with undifferentiated respiratory failure.

3.
Hum Mutat ; 40(7): 908-925, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30817854

RESUMO

Pathogenic de novo variants in the X-linked gene SLC35A2 encoding the major Golgi-localized UDP-galactose transporter required for proper protein and lipid glycosylation cause a rare type of congenital disorder of glycosylation known as SLC35A2-congenital disorders of glycosylation (CDG; formerly CDG-IIm). To date, 29 unique de novo variants from 32 unrelated individuals have been described in the literature. The majority of affected individuals are primarily characterized by varying degrees of neurological impairments with or without skeletal abnormalities. Surprisingly, most affected individuals do not show abnormalities in serum transferrin N-glycosylation, a common biomarker for most types of CDG. Here we present data characterizing 30 individuals and add 26 new variants, the single largest study involving SLC35A2-CDG. The great majority of these individuals had normal transferrin glycosylation. In addition, expanding the molecular and clinical spectrum of this rare disorder, we developed a robust and reliable biochemical assay to assess SLC35A2-dependent UDP-galactose transport activity in primary fibroblasts. Finally, we show that transport activity is directly correlated to the ratio of wild-type to mutant alleles in fibroblasts from affected individuals.

4.
Birth Defects Res ; 111(12): 822-828, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-30677250

RESUMO

BACKGROUND: The teratogenic effects of prenatal alcohol exposure (PAE) have been extensively documented over the course of 45 years of research and psychiatric problems are pervasive in this population. In adults with PAE, suicidal risk is high but less is known about the suicidal risk in adolescents with fetal alcohol spectrum disorders (FASD). This study describes the prevalence of suicidal ideation and serious suicide attempts in a sample of 54 adolescents between the ages of 13 and 18 years with FASD. METHODS: Adolescents were diagnosed with FASD using the Updated Clinical Guidelines for Diagnosing Fetal Alcohol Spectrum Disorders. The Children's Interview for Psychiatric Syndromes was used to identify those adolescents who experienced suicidal ideation and/or who had made a serious suicide attempt in the last 12 months. RESULTS: The prevalence of suicidal behaviors in this sample was high with 35.2% of teens reporting incidences of suicidal ideation and 13.0% reporting at least one serious suicide attempt in the past year. This finding is in contrast to the 17.2% and 2.4% for ideation and serious attempts, respectively, reported in the general U.S. adolescent population. Alarmingly, 29.2% of males with FASD reported a serious suicide attempt which was 19½ times higher than national norms for males. No females reported attempts. Number of home placements and the presence of a depressive disorder contributed to study outcomes. CONCLUSIONS: Findings demonstrate the significant risk for suicidality in this population, particularly adolescent males, and the need to assess and treat this life threatening behavior.

5.
Mol Genet Metab ; 124(4): 254-265, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29960856

RESUMO

Glycerol kinase (GK) is a multifunctional enzyme located at the interface of carbohydrate and fat metabolism. It contributes to both central carbon metabolism and adipogenesis; specifically, through its role as the ATP-stimulated translocation promoter (ASTP). GK overexpression leads to increased ASTP activity and increased fat storage in H4IIE cells. We performed metabolic flux analysis in human GK-overexpressing H4IIE cells and found that overexpressing cells had significantly altered fluxes through central carbon and lipid metabolism including increased flux through the pentose phosphate pathway and increased production of lipids. We also observed an equal contribution of glycerol to carbohydrate metabolism in all cell lines, suggesting that GK's alternate functions rather than its enzymatic function are important for these processes. To further elucidate the contributions of the enzymatic (phosphorylation) and alternative (ASTP) functions of GK in adipogenesis, we performed experiments on mammalian GK and E. coli GK. We determined that the ASTP function of GK (which is absent in E. coli GK) plays a greater role than the enzymatic activity in these processes. These studies further emphasize GK's diverse functionality and provides fundamental insights into the multiple protein functions of glycerol kinase.

6.
J Pediatr Genet ; 5(4): 220-224, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27895974

RESUMO

Craniofacial malformations include a variety of anomalies, including cleft lip with or without cleft palate, craniosynostosis, microtia, and hemifacial microsomia. All of these anomalies can be either isolated or part of a defined genetic syndrome. A clinical geneticist or genetic counselor should be a member of the craniofacial team to help determine which patients have isolated anomalies and which are likely to have a syndrome. They would then arrange for the appropriate genetic testing to confirm the diagnosis of the specific syndrome. The identification of the specific syndrome is important for the overall care of the patient (as it identifies risk for other medical problems such as congenital heart defect) that will have to be taken into account in the care of the craniofacial malformation. In addition, knowing the specific syndrome will allow the family to understand how this happened to their child and the recurrence risk for future pregnancies. With the advent of new technologies, there are now many types of genetic testing available (including, karyotype, fluorescence in situ hybridization, chromosomal microarrays, and next generation sequencing) and the medical geneticist and genetic counselor can determine which specific testing is needed for a given patient.

7.
Mol Genet Metab ; 119(3): 288-292, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27746033

RESUMO

Mathematical modeling approaches have been commonly used in complex signaling pathway studies such as the insulin signal transduction pathway. Our expanded mathematical model of the insulin signal transduction pathway was previously shown to effectively predict glucose clearance rates using mRNA levels of key components of the pathway in a mouse model. In this study, we re-optimized and applied our expanded model to study insulin sensitivity in other species and tissues (human skeletal muscle) with altered protein activities of insulin signal transduction pathway components. The model has now been optimized to predict the effect of short term exercise on insulin sensitivity for human test subjects with obesity or type II diabetes mellitus. A comparison between our extended model and the original model showed that our model better simulates the GLUT4 translocation events of the insulin signal transduction pathway and glucose uptake as a clinically relevant model output. Results from our extended model correlate with O'Gorman's published in-vivo results. This study demonstrates the ability to adapt this model to study insulin sensitivity to many biological systems (human skeletal muscle and mouse liver) with minimal changes in the model parameters.


Assuntos
Diabetes Mellitus Tipo 2/genética , Resistência à Insulina/genética , Modelos Teóricos , Obesidade/genética , Animais , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/patologia , Humanos , Insulina/genética , Camundongos , Obesidade/complicações , Obesidade/patologia , Transdução de Sinais
8.
Hum Mol Genet ; 25(R2): R86-R93, 2016 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-27346519

RESUMO

Craniofacial development is an intricate process of patterning, morphogenesis, and growth that involves many tissues within the developing embryo. Genetic misregulation of these processes leads to craniofacial malformations, which comprise over one-third of all congenital birth defects. Significant advances have been made in the clinical management of craniofacial disorders, but currently very few treatments specifically target the underlying molecular causes. Here, we review recent studies in which modeling of craniofacial disorders in primary patient cells, patient-derived induced pluripotent stem cells (iPSCs), and mice have enhanced our understanding of the etiology and pathophysiology of these disorders while also advancing therapeutic avenues for their prevention.

9.
Alcohol Clin Exp Res ; 40(8): 1744-51, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27219498

RESUMO

BACKGROUND: Project Step Up proposed to reduce alcohol consumption and alcohol-related negative outcomes in adolescents with fetal alcohol spectrum disorders (FASD). METHODS: The 54 participants (30 females, 24 males) were assigned to either Project Step Up Intervention (SUI) or Control conditions and were assessed prior to intervention, immediately following intervention, and at 3-month follow-up. Adolescents in the SUI condition participated in a 6-week, 60-minute group intervention that provided alcohol education and promoted adaptive responses to alcohol-related social pressures. Caregivers attended concurrent but separate sessions on the effects of prenatal alcohol exposure on the brain and how to handle parenting challenges associated with alcohol use in teens with FASD. RESULTS: Thirty-three percent (n = 18) of adolescents were classified as light/moderate drinkers, and 67% (n = 36) were abstinent/infrequent drinkers based on their lifetime drinking histories. Results revealed a significant decrease in self-reported alcohol risk and in alcohol-related negative behaviors (Cohen's d = 1.08 and 0.99) in light/moderate drinkers in the SUI compared to the Control group. These results were partially sustained at 3-month follow-up. Furthermore, adolescents in the abstinent/infrequent group exhibited no increase in alcohol-related outcomes suggesting that the group intervention used in this study was not iatrogenic. CONCLUSIONS: The success of this treatment development study provides preliminary support for effective treatment of adolescents with FASD to prevent or reduce alcohol use and its negative consequences in this high risk population.


Assuntos
Abstinência de Álcool , Consumo de Bebidas Alcoólicas/terapia , Intervenção Médica Precoce/métodos , Transtornos do Espectro Alcoólico Fetal/diagnóstico , Transtornos do Espectro Alcoólico Fetal/terapia , Adolescente , Abstinência de Álcool/psicologia , Abstinência de Álcool/tendências , Consumo de Bebidas Alcoólicas/psicologia , Intervenção Médica Precoce/tendências , Feminino , Transtornos do Espectro Alcoólico Fetal/psicologia , Seguimentos , Humanos , Masculino , Projetos Piloto , Gravidez , Efeitos Tardios da Exposição Pré-Natal/diagnóstico , Efeitos Tardios da Exposição Pré-Natal/psicologia , Efeitos Tardios da Exposição Pré-Natal/terapia , Autorrelato , Resultado do Tratamento
10.
Hum Mutat ; 37(2): 148-54, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26507355

RESUMO

Mandibulofacial dysostosis with microcephaly (MFDM) is a multiple malformation syndrome comprising microcephaly, craniofacial anomalies, hearing loss, dysmorphic features, and, in some cases, esophageal atresia. Haploinsufficiency of a spliceosomal GTPase, U5-116 kDa/EFTUD2, is responsible. Here, we review the molecular basis of MFDM in the 69 individuals described to date, and report mutations in 38 new individuals, bringing the total number of reported individuals to 107 individuals from 94 kindreds. Pathogenic EFTUD2 variants comprise 76 distinct mutations and seven microdeletions. Among point mutations, missense substitutions are infrequent (14 out of 76; 18%) relative to stop-gain (29 out of 76; 38%), and splicing (33 out of 76; 43%) mutations. Where known, mutation origin was de novo in 48 out of 64 individuals (75%), dominantly inherited in 12 out of 64 (19%), and due to proven germline mosaicism in four out of 64 (6%). Highly penetrant clinical features include, microcephaly, first and second arch craniofacial malformations, and hearing loss; esophageal atresia is present in an estimated ∼27%. Microcephaly is virtually universal in childhood, with some adults exhibiting late "catch-up" growth and normocephaly at maturity. Occasionally reported anomalies, include vestibular and ossicular malformations, reduced mouth opening, atrophy of cerebral white matter, structural brain malformations, and epibulbar dermoid. All reported EFTUD2 mutations can be found in the EFTUD2 mutation database (http://databases.lovd.nl/shared/genes/EFTUD2).


Assuntos
Anormalidades Múltiplas/genética , Perda Auditiva/genética , Deficiência Intelectual/genética , Disostose Mandibulofacial/genética , Microcefalia/genética , Mutação , Fatores de Alongamento de Peptídeos/genética , Ribonucleoproteína Nuclear Pequena U5/genética , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/patologia , Motivos de Aminoácidos , Bases de Dados Genéticas , Expressão Gênica , Haploinsuficiência , Perda Auditiva/diagnóstico , Perda Auditiva/patologia , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/patologia , Disostose Mandibulofacial/diagnóstico , Disostose Mandibulofacial/patologia , Microcefalia/diagnóstico , Microcefalia/patologia , Modelos Moleculares , Dados de Sequência Molecular , Penetrância , Fenótipo , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , Processamento de RNA , Spliceossomos/genética
11.
Mol Genet Metab Rep ; 4: 42-45, 2015 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-26309814

RESUMO

Glycerol kinase deficiency (GKD) is an X-linked inborn error of metabolism at the interface of fat and carbohydrate metabolism. We report a male patient with GKD and a novel insertion of TT in exon 5 at position 378 of the GK cDNA (378-379insTT). This resulted in a premature stop codon and 0.8% normal GK activity. The mother is a carrier for this mutation and had gestational diabetes requiring insulin during this pregnancy but not in her previous pregnancy. Given the association between GKD and type 2 diabetes mellitus, it is interesting that the mother had gestational diabetes while carrying an affected fetus. Therefore, GKD is another disease where there may be a maternal-fetal interaction based on genotype. Further investigations may help elucidate the role of GKD in the carrier mother's gestational diabetes. In addition, these studies will provide better-informed counseling to families with GKD regarding the risk to carrier females.

12.
Mol Genet Metab ; 114(1): 66-72, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25468647

RESUMO

Mathematical models of biological pathways facilitate a systems biology approach to medicine. However, these models need to be updated to reflect the latest available knowledge of the underlying pathways. We developed a mathematical model of the insulin signal transduction pathway by expanding the last major previously reported model and incorporating pathway components elucidated since the original model was reported. Furthermore, we show that inputting gene expression data of key components of the insulin signal transduction pathway leads to sensible predictions of glucose clearance rates in agreement with reported clinical measurements. In one set of simulations, our model predicted that glycerol kinase knockout mice have reduced GLUT4 translocation, and consequently, reduced glucose uptake. Additionally, a comparison of our extended model with the original model showed that the added pathway components improve simulations of glucose clearance rates. We anticipate this expanded model to be a useful tool for predicting insulin sensitivity in mammalian tissues with altered expression protein phosphorylation or mRNA levels of insulin signal transduction pathway components.


Assuntos
Glucose/metabolismo , Resistência à Insulina , Insulina/metabolismo , Modelos Biológicos , Transdução de Sinais , Animais , Perfilação da Expressão Gênica , Transportador de Glucose Tipo 4/genética , Transportador de Glucose Tipo 4/metabolismo , Glicerol Quinase/genética , Resistência à Insulina/genética , Camundongos , Camundongos Knockout , Fosforilação
13.
JAMA ; 312(18): 1880-7, 2014 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-25326637

RESUMO

IMPORTANCE: Clinical exome sequencing (CES) is rapidly becoming a common molecular diagnostic test for individuals with rare genetic disorders. OBJECTIVE: To report on initial clinical indications for CES referrals and molecular diagnostic rates for different indications and for different test types. DESIGN, SETTING, AND PARTICIPANTS: Clinical exome sequencing was performed on 814 consecutive patients with undiagnosed, suspected genetic conditions at the University of California, Los Angeles, Clinical Genomics Center between January 2012 and August 2014. Clinical exome sequencing was conducted as trio-CES (both parents and their affected child sequenced simultaneously) to effectively detect de novo and compound heterozygous variants or as proband-CES (only the affected individual sequenced) when parental samples were not available. MAIN OUTCOMES AND MEASURES: Clinical indications for CES requests, molecular diagnostic rates of CES overall and for phenotypic subgroups, and differences in molecular diagnostic rates between trio-CES and proband-CES. RESULTS: Of the 814 cases, the overall molecular diagnosis rate was 26% (213 of 814; 95% CI, 23%-29%). The molecular diagnosis rate for trio-CES was 31% (127 of 410 cases; 95% CI, 27%-36%) and 22% (74 of 338 cases; 95% CI, 18%-27%) for proband-CES. In cases of developmental delay in children (<5 years, n = 138), the molecular diagnosis rate was 41% (45 of 109; 95% CI, 32%-51%) for trio-CES cases and 9% (2 of 23, 95% CI, 1%-28%) for proband-CES cases. The significantly higher diagnostic yield (P value = .002; odds ratio, 7.4 [95% CI, 1.6-33.1]) of trio-CES was due to the identification of de novo and compound heterozygous variants. CONCLUSIONS AND RELEVANCE: In this sample of patients with undiagnosed, suspected genetic conditions, trio-CES was associated with higher molecular diagnostic yield than proband-CES or traditional molecular diagnostic methods. Additional studies designed to validate these findings and to explore the effect of this approach on clinical and economic outcomes are warranted.


Assuntos
Exoma , Doenças Genéticas Inatas/diagnóstico , Técnicas de Diagnóstico Molecular , Doenças Raras/diagnóstico , Adolescente , Adulto , Criança , Pré-Escolar , Deficiências do Desenvolvimento/genética , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Mutação , Doenças Raras/genética , Análise de Sequência de DNA/métodos
14.
Am J Med Genet A ; 164A(12): 3076-82, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25256560

RESUMO

Deletions of chromosome 17q12 [OMIM 614527] encompass a wide range of phenotypes, including renal cysts, diabetes mellitus, pancreatic structural abnormalities, genital tract anomalies, developmental delay, learning difficulties, and more recently, autism spectrum disorder and schizophrenia. To date, gastrointestinal malformations have not been fully characterized in this syndrome. In this case report, we describe a four-year-old girl with a 17q12 microdeletion who was born with duodenal atresia, bilateral renal cysts, left kidney dysplasia, a midline cystic structure at the conus medullaris, and dysmorphic features. Both the patient and her affected father were found to have a deletion of 17q12, which encompasses the HNF1B (hepatocyte nuclear factor beta). It is hypothesized that HNF1B may play a role in intestinal differentiation and development. Our clinical report further expands the pre-and post-natal presentation of this rare microdeletion syndrome.


Assuntos
Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Aberrações Cromossômicas , Cromossomos Humanos Par 17/genética , Obstrução Duodenal/genética , Fator 1-beta Nuclear de Hepatócito/deficiência , Fenótipo , Feminino , Fator 1-beta Nuclear de Hepatócito/genética , Humanos , Atresia Intestinal , Análise em Microsséries , Síndrome
15.
Mol Genet Metab Rep ; 1: 373-377, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-27896111

RESUMO

Both adrenal catecholamines and steroids are known to be involved in the stress response, immune function, blood pressure and energy homeostasis. The response to stress is characterized by the activation of the hypothalamus-pituitary-adrenal (HPA) axis and the sympathetic-adrenomedullary system, though the correlation with activation and development is not well understood. We evaluated the stress response of both cortisol and catecholamines during development in zebrafish. Zebrafish at two different stages of development were stressed in one of two different ways and cortisol and catecholamine were measured. Cortisol was measured by enzyme immune assay and catecholamine was measured by ELISA. Our results show that stress responses are delayed until after the synthesis of both cortisol and catecholamines. These observations suggest that the development of HPA axis may be required for the acquisition of the stress response for cortisol and catecholamines.

16.
PLoS One ; 8(9): e71664, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24039719

RESUMO

In Drosophila, RNAi targeting of either dGyk or dGK can result in two alternative phenotypes: adult glycerol hypersensitivity or larval lethality. Here we compare these two phenotypes at the level of glycerol kinase (GK) phosphorylation activity, dGyk and dGK-RNA expression, and glycerol levels. We found both phenotypes exhibit reduced but similar levels of GK phosphorylation activity. Reduced RNA expression levels of dGyk and dGK corresponded with RNAi progeny that developed into glycerol hypersensitive adult flies. However, quantification of dGyk/dGK expression levels for the larval lethality phenotype revealed unexpected levels possibly due to a compensatory mechanism between dGyk and dGK or RNAi inhibition. The enzymatic role of glycerol kinase converts glycerol to glycerol 3-phosphate. As expected, elevated glycerol levels were observed in larvae that went on to develop into glycerol hypersensitive adults. Interestingly, larvae that died before eclosion revealed extremely low glycerol levels. Further characterization identified a wing phenotype that is enhanced by a dGpdh null mutation, indicating disrupted glycerol metabolism underlies the wing phenotype. In humans, glycerol kinase deficiency (GKD) exhibits a wide range of phenotypic variation with no obvious genotype-phenotype correlations. Additionally, disease severity often does not correlate with GK phosphorylation activity. It is intriguing that both human GKD patients and our GKD Drosophila model show a range of phenotype severity. Additionally, the lack of correlation between GK phosphorylation and dGyk/dGK-RNA expression with phenotypic severity suggests further study including understanding the alternative functions of the GK protein, could provide insights into the complex pathogenic mechanism observed in human GKD patients.


Assuntos
Proteínas de Drosophila/genética , Drosophila/enzimologia , Glicerol Quinase/genética , Glicerol/metabolismo , Interferência de RNA , Animais , Drosophila/genética , Proteínas de Drosophila/deficiência , Técnicas de Silenciamento de Genes , Genes Letais , Glicerol Quinase/deficiência , Glicerolfosfato Desidrogenase/genética , Glicerolfosfato Desidrogenase/metabolismo , Humanos , Larva/enzimologia , Larva/genética , Fenótipo , Asas de Animais/anormalidades , Asas de Animais/enzimologia
17.
Am J Med Genet A ; 161A(7): 1773-8, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23696469

RESUMO

Deletions of the long arm of chromosome 18 have been previously reported in many patients. Most cases involve the more distal regions of the long arm (18q21.1->qter). However, proximal interstitial deletions involving 18q11.2 are extremely rare. Here we report on a 14-month-old female with a 4.7 Mb (19,667,062-24,401,876 hg19) de novo interstitial deletion within chromosomal band 18q11.2, which includes GATA6 and 24 other RefSeq genes. The clinical features of our patient include complex congenital heart defects, a double outlet right ventricle, a subaortic ventricular septal defect, D-malposed great arteries, an atrial septal defect, a dysplastic aortic valve and patent ductus arteriosus. In addition, she had renal anomalies-a duplicated collecting system on the left and mild right hydronephrosis. These heart and renal defects are not reported in other patients with 18q proximal interstitial deletions. Heterozygous point mutations in GATA6, encoding for a zinc finger transcription factor, have been shown to cause congenital heart defects. Given the well-established biological role of GATA6 in cardiac development, a deletion of GATA6 is very likely responsible for our patient's complex congenital heart defects. This is the smallest and most proximal 18q11.2 deletion involving GATA6 that is associated with complex congenital heart disease and renal anomalies.


Assuntos
Transtornos Cromossômicos/genética , Cardiopatias Congênitas/genética , Rim/anormalidades , Deleção Cromossômica , Transtornos Cromossômicos/etiologia , Cromossomos Humanos Par 18/genética , Feminino , Fator de Transcrição GATA6/genética , Humanos , Lactente , Recém-Nascido , Gravidez
18.
Am J Med Genet A ; 161A(5): 1167-72, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23532965

RESUMO

Pierre Robin sequence (PRS) is a malformation pattern characterized by the core triad of retrognathia, glossoptosis, and cleft palate that causes difficulty in glossopharyngeal-laryngeal-vagal functions. The etiology of PRS remains largely unknown; previous reports have suggested that it is caused by intrauterine constriction or external conditions such as oligohydramnios, breech position, or abnormal uterine anatomy. Genetic causes include occurrence as a manifestation of many single gene conditions and chromosomal rearrangements. Positional effect on some loci or genes, including SOX9 has also been posited as a cause. Here, we report on an 18-month-old girl born with isolated PRS. Clinical chromosome microarray analysis (CMA) revealed a maternally inherited ~623 kb microdeletion that is -725 kb upstream of 5' SOX9 at chromosome locus 17q24.3. Her mother had cleft palate. This region, although devoid of any genes, is known to have a position effect on SOX9 due to elimination of highly conserved non-coding cis-regulatory elements. This report supports the evidence that deregulation of an intact SOX9 coding region is a cause of or associated with isolated PRS, and provides further evidence that CMA in the clinical setting is a powerful tool in detecting microdeletions in gene "desert" regions that have pathogenic position effect on specific genes.


Assuntos
Fibromatose Gengival/genética , Hipertricose/genética , Síndrome de Pierre Robin/genética , Fatores de Transcrição SOX9/genética , Deleção Cromossômica , Cromossomos Humanos Par 17/genética , Feminino , Humanos , Lactente , Análise de Sequência com Séries de Oligonucleotídeos
19.
Cleft Palate Craniofac J ; 50(5): 618-22, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22449124

RESUMO

We report on a 3½-year-old African American female with a 1.63 Mb microdeletion in 5q35.2-q35.3. This deletion includes NSD1, the gene that causes Sotos syndrome. The patient has unilateral cleft lip and palate (CLP) status postrepair, an unrepaired alveolar cleft, speech delay, global developmental delay, macrocephaly, mild cerebral palsy, and a patent ductus arteriosus status postrepair. Dysmorphic features include a prominent forehead and midface hypoplasia. This is one of the first cases of CLP associated with Sotos syndrome and emphasizes the utility of chromosomal microarray analysis in patients with more than isolated CLP in the Craniofacial Clinic.


Assuntos
Fenda Labial , Síndrome de Sotos , Fissura Palatina , Humanos
20.
PLoS One ; 7(3): e31779, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22427807

RESUMO

Glycerol kinase plays a critical role in metabolism by converting glycerol to glycerol 3-phosphate in an ATP dependent reaction. In humans, glycerol kinase deficiency results in a wide range of phenotypic variability; patients can have severe metabolic and CNS abnormalities, while others possess hyperglycerolemia and glyceroluria with no other apparent phenotype. In an effort to help understand the pathogenic mechanisms underlying the phenotypic variation, we have created a Drosophila model for glycerol kinase deficiency by RNAi targeting of dGyk (CG18374) and dGK (CG7995). As expected, RNAi flies have reduced glycerol kinase RNA expression, reduced phosphorylation activity and elevated glycerol levels. Further investigation revealed these flies to be hypersensitive to fly food supplemented with glycerol. Due to the hygroscopic nature of glycerol, we predict glycerol hypersensitivity is a result of greater susceptibility to desiccation, suggesting glycerol kinase to play an important role in desiccation resistance in insects. To evaluate a role for genetic modifier loci in determining severity of the glycerol hypersensitivity observed in knockdown flies, we performed a preliminary screen of lethal transposon insertion mutant flies using a glycerol hypersensitive survivorship assay. We demonstrate that this type of screen can identify both enhancer and suppressor genetic loci of glycerol hypersensitivity. Furthermore, we found that the glycerol hypersensitivity phenotype can be enhanced or suppressed by null mutations in eye pigmentation genes. Taken together, our data suggest proteins encoded by eye pigmentation genes play an important role in desiccation resistance and that eye pigmentation genes are strong modifiers of the glycerol hypersensitive phenotype identified in our Drosophila model for glycerol kinase deficiency.


Assuntos
Erros Inatos do Metabolismo dos Carboidratos/complicações , Modelos Animais de Doenças , Glicerol , Hipersensibilidade/etiologia , Pigmentação/genética , Análise de Variância , Animais , Animais Geneticamente Modificados , Primers do DNA/genética , Drosophila , Técnicas de Silenciamento de Genes , Glicerol Quinase/deficiência , Hipersensibilidade/genética , Hipoadrenocorticismo Familiar , Epitélio Pigmentado Ocular/metabolismo , Interferência de RNA , Reação em Cadeia da Polimerase em Tempo Real , Taxa de Sobrevida , Equilíbrio Hidroeletrolítico/genética , Equilíbrio Hidroeletrolítico/fisiologia
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