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1.
BMC Pediatr ; 19(1): 195, 2019 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-31196016

RESUMO

INTRODUCTION: Propionic acidemia (PA) and methylmalonic acidemia (MMA) are rare autosomal recessive inborn errors of metabolism characterized by hyperammonemia due to N-acetylglutamate synthase (NAGS) dysfunction. Carglumic acid (Carbaglu®; Orphan Europe Ltd.) is approved by the US Food and Drug Administration (USFDA) for the treatment of hyperammonemia due hepatic NAGS deficiency. Here we report the rationale and design of a phase IIIb trial that is aimed at determining the long-term efficacy and safety of carglumic acid in the management of PA and MMA. METHODS: This prospective, multicenter, open-label, randomized, parallel group phase IIIb study will be conducted in Saudi Arabia. Patients with PA or MMA (≤15 years of age) will be randomized 1:1 to receive twice daily carglumic acid (50 mg/kg/day) plus standard therapy (protein-restricted diet, L-carnitine, and metronidazole) or standard therapy alone for a 2-year treatment period. The primary efficacy outcome is the number of emergency room visits due to hyperammonemia. Safety will be assessed throughout the study and during the 1 month follow-up period after the study. DISCUSSION: Current guidelines recommend conservative medical treatment as the main strategy for the management of PA and MMA. Although retrospective studies have suggested that long-term carglumic acid may be beneficial in the management of PA and MMA, current literature lacks evidence for this indication. This clinical trial will determine the long-term safety and efficacy of carglumic acid in the management of PA and MMA. TRIAL REGISTRATION: King Abdullah International Medical Research Center ( KAIMRC ): (RC13/116) 09/1/2014. Saudi Food and Drug Authority (SFDA) (33066) 08/14/2014. ClinicalTrials.gov (identifier: NCT02426775) 04/22/2015.

2.
Clin Genet ; 95(2): 310-319, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30561787

RESUMO

Defects in the peroxisomes biogenesis and/or function result in peroxisomal disorders. In this study, we describe the largest Arab cohort to date (72 families) of clinically, biochemically and molecularly characterized patients with peroxisomal disorders. At the molecular level, we identified 43 disease-causing variants, half of which are novel. The founder nature of many of the variants allowed us to calculate the minimum disease burden for these disorders in our population ~1:30 000, which is much higher than previous estimates in other populations. Clinically, we found an interesting trend toward genotype/phenotype correlation in terms of long-term survival. Nearly half (40/75) of our peroxisomal disorders patients had documented survival beyond 1 year of age. Most unusual among the long-term survivors was a multiplex family in which the affected members presented as adults with non-specific intellectual disability and epilepsy. Other unusual presentations included the very recently described peroxisomal fatty acyl-CoA reductase 1 disorder as well as CRD, spastic paraparesis, white matter (CRSPW) syndrome. We conclude that peroxisomal disorders are highly heterogeneous in their clinical presentation. Our data also confirm the demonstration that milder forms of Zellweger spectrum disorders cannot be ruled out by the "gold standard" very long chain fatty acids assay, which highlights the value of a genomics-first approach in these cases.

3.
J Child Neurol ; 33(11): 713-717, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30014764

RESUMO

Propionic acidemia is an inborn error of metabolism that is inherited in an autosomal recessive manner. It is characterized by a deficient propionyl-CoA carboxylase due to mutations in either of its beta or alpha subunits. In the literature, there is a clear association between propionic acidemia and epilepsy. In this cohort, we retrospectively reviewed the data of 14 propionic acidemia patients in Saudi Arabia and compared the findings to those of former studies. Six of the 14 (43%) patients developed epileptic seizure, mainly focal seizures. All patients were responsive to conventional antiepileptic drugs as their seizures are controlled. The predominant electroencephalographic (EEG) findings were diffuse slowing in 43% and multifocal epileptiform discharges in 14% of the patients. In 1 patient, burst suppression pattern was detected, a pattern never before reported in patients with propionic acidemia. Brain magnetic resonance imaging (MRI) findings mainly consisted of signal changes of the basal ganglia (36%), generalized brain atrophy (43%), and delayed myelination (43%).The most common genotype in our series is the homozygous missense mutation in the PCCA gene (c.425G>A; p. Gly142Asp). However, there is no clear genotype-seizure correlation. We conclude that seizure is not an uncommon finding in patients with propionic acidemia and not difficult to control. Additional studies are needed to further elaborate on genotype-seizure correlation.

4.
Genet Med ; 20(11): 1328-1333, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29565419

RESUMO

PURPOSE: Whole-exome sequencing (WES) and whole-genome sequencing (WGS) are used to diagnose genetic and inherited disorders. However, few studies comparing the detection rates of WES and WGS in clinical settings have been performed. METHODS: Variant call format files were generated and raw data analysis was performed in cases in which the final molecular results showed discrepancies. We classified the possible explanations for the discrepancies into three categories: the time interval between the two tests, the technical limitations of WES, and the impact of the sequencing system type. RESULTS: This cohort comprised 108 patients with negative array comparative genomic hybridization and negative or inconclusive WES results before WGS was performed. Ten (9%) patients had positive WGS results. However, after reanalysis the WGS hit rate decreased to 7% (7 cases). In four cases the variants were identified by WES but missed for different reasons. Only 3 cases (3%) were positive by WGS but completely unidentified by WES. CONCLUSION: In this study, we showed that 30% of the positive cases identified by WGS could be identified by reanalyzing the WES raw data, and WGS achieved an only 7% higher detection rate. Therefore, until the cost of WGS approximates that of WES, reanalyzing WES raw data is recommended before performing WGS.

5.
Appl Clin Genet ; 11: 9-14, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29467581

RESUMO

Tetrasomy 18p syndrome (Online Mendelian Inheritance in Man 614290) is a very rare chromosomal disorder that is caused by the presence of isochromosome 18p, which is a supernumerary marker composed of two copies of the p arm of chromosome 18. Most tetrasomy 18p cases are de novo cases; however, familial cases have also been reported. It is characterized mainly by developmental delays, cognitive impairment, hypotonia, typical dysmorphic features, and other anomalies. Herein, we report de novo tetrasomy 18p in a 9-month-old boy with dysmorphic features, microcephaly, growth delay, hypotonia, and cerebellar and renal malformations. We compared our case with previously reported ones in the literature. Clinicians should consider tetrasomy 18p in any individual with dysmorphic features and cardiac, skeletal, and renal abnormalities. To the best of our knowledge, we report for the first time an association of this syndrome with partial agenesis of cerebellar vermis.

6.
Genet Med ; 20(10): 1175-1185, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29469822

RESUMO

PURPOSE: To characterize the molecular genetics of autosomal recessive Noonan syndrome. METHODS: Families underwent phenotyping for features of Noonan syndrome in children and their parents. Two multiplex families underwent linkage analysis. Exome, genome, or multigene panel sequencing was used to identify variants. The molecular consequences of observed splice variants were evaluated by reverse-transcription polymerase chain reaction. RESULTS: Twelve families with a total of 23 affected children with features of Noonan syndrome were evaluated. The phenotypic range included mildly affected patients, but it was lethal in some, with cardiac disease and leukemia. All of the parents were unaffected. Linkage analysis using a recessive model supported a candidate region in chromosome 22q11, which includes LZTR1, previously shown to harbor mutations in patients with Noonan syndrome inherited in a dominant pattern. Sequencing analyses of 21 live-born patients and a stillbirth identified biallelic pathogenic variants in LZTR1, including putative loss-of-function, missense, and canonical and noncanonical splicing variants in the affected children, with heterozygous, clinically unaffected parents and heterozygous or normal genotypes in unaffected siblings. CONCLUSION: These clinical and genetic data confirm the existence of a form of Noonan syndrome that is inherited in an autosomal recessive pattern and identify biallelic mutations in LZTR1.

7.
JIMD Rep ; 40: 47-53, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-28980192

RESUMO

BACKGROUND: Very long chain acyl CoA dehydrogenase (VLCAD) deficiency (OMIM#201475) is an autosomal recessive disorder of fatty acid beta oxidation caused by defect in the ACADVL. The aim of this study was to analyze the clinical, biochemical, and molecular features of VLCAD deficiency in Saudi Arabia, including the treatment and outcome. METHODS: We carried out a retrospective chart review analysis of 37 VLCAD deficiency patients from two tertiary centers in Saudi Arabia, over a 14-year period (2002-2016). Twenty-three patients were managed at King Abdul-Aziz Medical City and fourteen patients at King Fahad Medical City. RESULTS: Severe early onset VLCAD deficiency is the most frequent phenotype in our patients, caused by four different mutations in ACADVL; 31 patients (83.7%) had a homozygous nonsense mutation in exon 2 of ACADVL c.65C>A;p. Ser22X. Twenty-three patients died before the age of 2 years, despite early detection by newborn screening and implementation of treatment, including supplementation with medium chain triglycerides. CONCLUSION: This study reports the clinical, biochemical, molecular findings, treatment, and outcome of patients with VLCAD deficiency over the last 14 years. We identified the most common variant and one new variant in ACADVL. Despite early diagnosis and treatment, the outcome of VLCAD deficiency in this Saudi Arabian population remains poor. Preventive measures, such as prenatal diagnosis, could be implemented.

8.
Genet Med ; 20(5): 536-544, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29048421

RESUMO

PurposeHearing loss is more prevalent in the Saudi Arabian population than in other populations; however, the full range of genetic etiologies in this population is unknown. We report the genetic findings from 33 Saudi hearing-loss probands of tribal ancestry, with predominantly prelingual severe to profound hearing loss.MethodsTesting was performed over the course of 2012-2016, and involved initial GJB2 sequence and GJB6-D13S1830 deletion screening, with negative cases being reflexed to a next-generation sequencing panel with 70, 71, or 87 hearing-loss genes.ResultsA "positive" result was reached in 63% of probands, with two recurrent OTOF variants (p.Glu57* and p.Arg1792His) accountable for a third of all "positive" cases. The next most common cause was pathogenic variants in MYO7A and SLC26A4, each responsible for three "positive" cases. Interestingly, only one "positive" diagnosis had a DFNB1-related cause, due to a homozygous GJB6-D13S1830 deletion, and no sequence variants in GJB2 were detected.ConclusionOur findings implicate OTOF as a potential major contributor to hearing loss in the Saudi population, while highlighting the low contribution of GJB2, thus offering important considerations for clinical testing strategies for Saudi patients. Further screening of Saudi patients is needed to characterize the genetic spectrum in this population.


Assuntos
Surdez/epidemiologia , Surdez/genética , Variação Genética , Proteínas de Membrana/genética , Adolescente , Adulto , Alelos , Substituição de Aminoácidos , Criança , Pré-Escolar , Estudos de Coortes , Conexinas/genética , Surdez/diagnóstico , Testes Genéticos , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Linhagem , Fenótipo , Vigilância da População , Arábia Saudita/epidemiologia , Adulto Jovem
10.
Hum Genet ; 136(4): 377-386, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28251352

RESUMO

Impairment of ubiquitin-proteasome system activity involving ubiquitin ligase genes UBE3A, UBE3B, and HUWE1 and deubiquitinating enzyme genes USP7 and USP9X has been reported in patients with neurodevelopmental delays. To date, only a handful of single-nucleotide variants (SNVs) and copy-number variants (CNVs) involving TRIP12, encoding a member of the HECT domain E3 ubiquitin ligases family on chromosome 2q36.3 have been reported. Using chromosomal microarray analysis and whole-exome sequencing (WES), we have identified, respectively, five deletion CNVs and four inactivating SNVs (two frameshifts, one missense, and one splicing) in TRIP12. Seven of these variants were found to be de novo; parental studies could not be completed in two families. Quantitative PCR analyses of the splicing mutation showed a dramatically decreased level of TRIP12 mRNA in the proband compared to the family controls, indicating a loss-of-function mechanism. The shared clinical features include intellectual disability with or without autistic spectrum disorders, speech delay, and facial dysmorphism. Our findings demonstrate that E3 ubiquitin ligase TRIP12 plays an important role in nervous system development and function. The nine presented pathogenic variants further document that TRIP12 haploinsufficiency causes a childhood-onset neurodevelopmental disorder. Finally, our data enable expansion of the phenotypic spectrum of ubiquitin-proteasome dependent disorders.


Assuntos
Transtorno do Espectro Autista/genética , Proteínas de Transporte/genética , Facies , Haploinsuficiência , Deficiência Intelectual/genética , Transtornos do Desenvolvimento da Linguagem/genética , Ubiquitina-Proteína Ligases/genética , Adolescente , Transtorno do Espectro Autista/complicações , Criança , Pré-Escolar , Estudos de Coortes , Variações do Número de Cópias de DNA , Feminino , Humanos , Lactente , Deficiência Intelectual/complicações , Transtornos do Desenvolvimento da Linguagem/complicações , Masculino
11.
Nat Genet ; 49(4): 537-549, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28191891

RESUMO

To ensure efficient genome duplication, cells have evolved numerous factors that promote unperturbed DNA replication and protect, repair and restart damaged forks. Here we identify downstream neighbor of SON (DONSON) as a novel fork protection factor and report biallelic DONSON mutations in 29 individuals with microcephalic dwarfism. We demonstrate that DONSON is a replisome component that stabilizes forks during genome replication. Loss of DONSON leads to severe replication-associated DNA damage arising from nucleolytic cleavage of stalled replication forks. Furthermore, ATM- and Rad3-related (ATR)-dependent signaling in response to replication stress is impaired in DONSON-deficient cells, resulting in decreased checkpoint activity and the potentiation of chromosomal instability. Hypomorphic mutations in DONSON substantially reduce DONSON protein levels and impair fork stability in cells from patients, consistent with defective DNA replication underlying the disease phenotype. In summary, we have identified mutations in DONSON as a common cause of microcephalic dwarfism and established DONSON as a critical replication fork protein required for mammalian DNA replication and genome stability.


Assuntos
Replicação do DNA/genética , Proteínas de Ligação a DNA/genética , Nanismo/genética , Instabilidade Genômica/genética , Microcefalia/genética , Mutação/genética , Linhagem Celular , Dano ao DNA/genética , Feminino , Humanos , Masculino
12.
PLoS One ; 11(3): e0150555, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26974433

RESUMO

Axial spondylometaphyseal dysplasia (axial SMD) is an autosomal recessive disease characterized by dysplasia of axial skeleton and retinal dystrophy. We conducted whole exome sequencing and identified C21orf2 (chromosome 21 open reading frame 2) as a disease gene for axial SMD. C21orf2 mutations have been recently found to cause isolated retinal degeneration and Jeune syndrome. We found a total of five biallelic C21orf2 mutations in six families out of nine: three missense and two splicing mutations in patients with various ethnic backgrounds. The pathogenic effects of the splicing (splice-site and branch-point) mutations were confirmed on RNA level, which showed complex patterns of abnormal splicing. C21orf2 mutations presented with a wide range of skeletal phenotypes, including cupped and flared anterior ends of ribs, lacy ilia and metaphyseal dysplasia of proximal femora. Analysis of patients without C21orf2 mutation indicated genetic heterogeneity of axial SMD. Functional data in chondrocyte suggest C21orf2 is implicated in cartilage differentiation. C21orf2 protein was localized to the connecting cilium of the cone and rod photoreceptors, confirming its significance in retinal function. Our study indicates that axial SMD is a member of a unique group of ciliopathy affecting skeleton and retina.


Assuntos
Doenças Genéticas Inatas/genética , Mutação , Osteocondrodisplasias/genética , Proteínas/genética , Adolescente , Cartilagem/metabolismo , Cartilagem/patologia , Diferenciação Celular/genética , Criança , Pré-Escolar , Feminino , Regulação da Expressão Gênica , Doenças Genéticas Inatas/diagnóstico por imagem , Doenças Genéticas Inatas/metabolismo , Humanos , Masculino , Osteocondrodisplasias/diagnóstico por imagem , Osteocondrodisplasias/metabolismo , Fenótipo , Proteínas/metabolismo , Radiografia , Retina/metabolismo , Retina/patologia , Adulto Jovem
14.
Am J Hum Genet ; 94(1): 62-72, 2014 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-24360808

RESUMO

Joubert syndrome (JBTS) is a recessive ciliopathy in which a subset of affected individuals also have the skeletal dysplasia Jeune asphyxiating thoracic dystrophy (JATD). Here, we have identified biallelic truncating CSPP1 (centrosome and spindle pole associated protein 1) mutations in 19 JBTS-affected individuals, four of whom also have features of JATD. CSPP1 mutations explain ∼5% of JBTS in our cohort, and despite truncating mutations in all affected individuals, the range of phenotypic severity is broad. Morpholino knockdown of cspp1 in zebrafish caused phenotypes reported in other zebrafish models of JBTS (curved body shape, pronephric cysts, and cerebellar abnormalities) and reduced ciliary localization of Arl13b, further supporting loss of CSPP1 function as a cause of JBTS. Fibroblasts from affected individuals with CSPP1 mutations showed reduced numbers of primary cilia and/or short primary cilia, as well as reduced axonemal localization of ciliary proteins ARL13B and adenylyl cyclase III. In summary, CSPP1 mutations are a major cause of the Joubert-Jeune phenotype in humans; however, the mechanism by which these mutations lead to both JBTS and JATD remains unknown.


Assuntos
Proteínas de Ciclo Celular/genética , Doenças Cerebelares/genética , Cílios/genética , Síndrome de Ellis-Van Creveld/genética , Anormalidades do Olho/genética , Doenças Renais Císticas/genética , Proteínas Associadas aos Microtúbulos/genética , Mutação , Retina/anormalidades , Anormalidades Múltiplas , Adolescente , Animais , Cerebelo/anormalidades , Criança , Pré-Escolar , Cílios/patologia , Éxons , Feminino , Fibroblastos/citologia , Fibroblastos/metabolismo , Técnicas de Silenciamento de Genes , Humanos , Lactente , Masculino , Fenótipo , Análise de Sequência de DNA , Adulto Jovem , Peixe-Zebra/genética
15.
Am J Med Genet A ; 161A(9): 2244-9, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23897666

RESUMO

Spondylocostal dysotosis (SCD) is a rare developmental congenital abnormality of the axial skeleton. Mutation of genes in the Notch signaling pathway cause SCD types 1-5. Dextrocardia with situs inversus is a rare congenital malformation in which the thoracic and abdominal organs are mirror images of normal. Such laterality defects are associated with gene mutations in the Nodal signaling pathway or cilia assembly or function. We investigated two distantly related individuals with a rare combination of severe segmental defects of the vertebrae (SDV) and dextrocardia with situs inversus. We found that both individuals were homozygous for the same mutation in HES7, and that this mutation caused a significant reduction of HES7 protein function; HES7 mutation causes SCD4. Two other individuals with SDV from two unrelated families were found to be homozygous for the same mutation. Interestingly, although the penetrance of the vertebral defects was complete, only 3/7 had dextrocardia with situs inversus, suggesting randomization of left-right patterning. Two of the affected individuals presented with neural tube malformations including myelomeningocele, spina bifida occulta and/or Chiari II malformation. Such neural tube phenotypes are shared with the originally identified SCD4 patient, but have not been reported in the other forms of SCD. In conclusion, it appears that mutation of HES7 is uniquely associated with defects in vertebral, heart and neural tube formation, and this observation will help provide a discriminatory diagnostic guide in patients with SCD, as well as inform molecular genetic testing.


Assuntos
Anormalidades Múltiplas/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Dextrocardia/genética , Cardiopatias Congênitas/genética , Hérnia Diafragmática/genética , Mutação , Situs Inversus/genética , Anormalidades Múltiplas/diagnóstico , Substituição de Aminoácidos , Animais , Mapeamento Cromossômico , Hibridização Genômica Comparativa , Consanguinidade , Dextrocardia/diagnóstico , Feminino , Genótipo , Cardiopatias Congênitas/diagnóstico , Hérnia Diafragmática/diagnóstico , Humanos , Lactente , Recém-Nascido , Masculino , Camundongos , Linhagem , Fenótipo , Situs Inversus/diagnóstico
16.
Genet Med ; 14(12): 955-62, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22935719

RESUMO

BACKGROUND: Pediatric cataract is an important preventable blinding disease. Previous studies have estimated 10-25% of cases to be genetic in etiology. METHODS: In an effort to characterize the genetics of cataract in our population, we have conducted a comprehensive clinical and genomic analysis (including autozygome and exome analysis) on a series of 38 index patients. RESULTS: Pediatric cataract is genetic in at least 79% of the study families. Although crystallins accounted for most of the mutant alleles, mutations in other genes were encountered, including recessive mutations in genes that usually cause the disease in a dominant manner. In addition, several novel candidate genes (MFSD6L, AKR1E2, RNLS, and CYP51A1) were identified. CONCLUSION: Pediatric cataract is typically a genetic disease, usually autosomal recessive, in Saudi Arabia. Although defining a specific cataract phenotype can sometimes predict the genetic cause, genomic analysis is often required to unravel the causative mutation given the marked genetic heterogeneity. The identified novel candidate genes require independent confirmation in future studies.


Assuntos
Catarata/genética , Criança , Análise Mutacional de DNA , Proteínas de Ligação a DNA/genética , Exoma , Proteínas do Olho/genética , Feminino , Efeito Fundador , Estudos de Associação Genética , Genoma Humano , Homozigoto , Humanos , Proteínas de Filamentos Intermediários/genética , Masculino , Monoaminoxidase/genética , Mutação de Sentido Incorreto , N-Acetilglucosaminiltransferases/genética , Receptor EphA2/genética , Arábia Saudita , Esterol 14-Desmetilase/genética , Fatores de Transcrição/genética , Cadeia B de beta-Cristalina/genética
17.
J Med Genet ; 49(2): 126-37, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22241855

RESUMO

BACKGROUND: Joubert syndrome (JS) is a ciliopathy characterised by a distinctive brain malformation (the 'molar tooth sign'), developmental delay, abnormal eye movements and abnormal breathing pattern. Retinal dystrophy, cystic kidney disease, liver fibrosis and polydactyly are variably present, resulting in significant phenotypic heterogeneity and overlap with other ciliopathies. JS is also genetically heterogeneous, resulting from mutations in 13 genes. These factors render clinical/molecular diagnosis and management challenging. CC2D2A mutations are a relatively common cause of JS and also cause Meckel syndrome. The clinical consequences of CC2D2A mutations in patients with JS have been incompletely reported. METHODS: Subjects with JS from 209 families were evaluated to identify mutations in CC2D2A. Clinical and imaging features in subjects with CC2D2A mutations were compared with those in subjects without CC2D2A mutations and reports in the literature. RESULTS: 10 novel CC2D2A mutations in 20 subjects were identified; a summary is provided of all published CC2D2A mutations. Subjects with CC2D2A-related JS were more likely to have ventriculomegaly (p<0.0001) and seizures (p=0.024) than subjects without CC2D2A mutations. No mutation-specific genotype-phenotype correlations could be identified, but the findings confirm the observation that mutations that cause CC2D2A-related JS are predicted to be less deleterious than mutations that cause CC2D2A-related Meckel syndrome. Missense variants in the coiled-coil and C2 domains, as well as the C-terminal region, identify these regions as important for the biological mechanisms underlying JS. CONCLUSIONS: CC2D2A testing should be prioritised in patients with JS and ventriculomegaly and/or seizures. Patients with CC2D2A-related JS should be monitored for hydrocephalus and seizures.


Assuntos
Doenças Cerebelares/genética , Anormalidades do Olho/genética , Estudos de Associação Genética , Hidrocefalia/genética , Doenças Renais Císticas/genética , Proteínas/genética , Convulsões/genética , Anormalidades Múltiplas , Adolescente , Adulto , Alelos , Doenças Cerebelares/diagnóstico , Doenças Cerebelares/epidemiologia , Cerebelo/anormalidades , Criança , Pré-Escolar , Anormalidades do Olho/diagnóstico , Anormalidades do Olho/epidemiologia , Genótipo , Humanos , Hidrocefalia/diagnóstico , Lactente , Doenças Renais Císticas/diagnóstico , Doenças Renais Císticas/epidemiologia , Imagem por Ressonância Magnética , Neuroimagem , Fenótipo , Prevalência , Retina/anormalidades , Adulto Jovem
18.
Atherosclerosis ; 203(2): 466-71, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18774132

RESUMO

Arterial tortuosity syndrome is an autosomal recessive disorder characterized by severe tortuosity of greater and systemic arteries in affected individuals. In addition, patients display connective tissue features which include hyperextensible skin, hypermobility of joints and characteristic facial features. This syndrome is caused by mutation in SLC2A10 gene which encodes for the facilitative glucose transporter, GLUT10. We describe seven patients of two unrelated Saudi Arabian families who display tortuosity, dilatation and stenosis of arteries, pulmonary hypertension and other cardiovascular manifestations. These patients exhibit characteristic connective tissue phenotypes and distinctive facial features. In the single patient of Family 1, sequencing of the candidate gene, SLC2A10, identified a novel missense c.313C>T mutation encoding a p.Arg105Cys substitution in the second extracellular domain of GLUT10. The Arg105 in GLUT10 is highly conserved across species and its replacement with cysteine is predicted to be pathogenic. In the second family, all of the six affected individuals carry recurrent c.243C>G missense mutation encoding a p.Ser81Arg change in the third transmembrane domain of GLUT10. The present study suggests that there exists an intra- and inter-familial phenotypic variability in arterial tortuosity patients carrying identical or different mutations in SLC2A10 gene. While skin hyperextensibility, small joint hypermobility, and facial features are similarly expressed in these patients, there is a range of other phenotypes which include arterial tortuosity and associated complications, and abnormalities of other organs.


Assuntos
Doenças do Tecido Conjuntivo/genética , Proteínas Facilitadoras de Transporte de Glucose/genética , Mutação de Sentido Incorreto , Mutação , Artérias/patologia , Constrição Patológica , Análise Mutacional de DNA , Saúde da Família , Feminino , Homozigoto , Humanos , Masculino , Fenótipo , Arábia Saudita , Síndrome
19.
Am J Hum Genet ; 83(5): 559-71, 2008 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-18950740

RESUMO

Joubert syndrome and related disorders (JSRD) are primarily autosomal-recessive conditions characterized by hypotonia, ataxia, abnormal eye movements, and intellectual disability with a distinctive mid-hindbrain malformation. Variable features include retinal dystrophy, cystic kidney disease, and liver fibrosis. JSRD are included in the rapidly expanding group of disorders called ciliopathies, because all six gene products implicated in JSRD (NPHP1, AHI1, CEP290, RPGRIP1L, TMEM67, and ARL13B) function in the primary cilium/basal body organelle. By using homozygosity mapping in consanguineous families, we identify loss-of-function mutations in CC2D2A in JSRD patients with and without retinal, kidney, and liver disease. CC2D2A is expressed in all fetal and adult tissues tested. In ciliated cells, we observe localization of recombinant CC2D2A at the basal body and colocalization with CEP290, whose cognate gene is mutated in multiple hereditary ciliopathies. In addition, the proteins can physically interact in vitro, as shown by yeast two-hybrid and GST pull-down experiments. A nonsense mutation in the zebrafish CC2D2A ortholog (sentinel) results in pronephric cysts, a hallmark of ciliary dysfunction analogous to human cystic kidney disease. Knockdown of cep290 function in sentinel fish results in a synergistic pronephric cyst phenotype, revealing a genetic interaction between CC2D2A and CEP290 and implicating CC2D2A in cilium/basal body function. These observations extend the genetic spectrum of JSRD and provide a model system for studying extragenic modifiers in JSRD and other ciliopathies.


Assuntos
Anormalidades Múltiplas/genética , Antígenos de Neoplasias/metabolismo , Mutação , Proteínas de Neoplasias/metabolismo , Proteínas/genética , Proteínas/metabolismo , Antígenos de Neoplasias/genética , Ataxia/genética , Cerebelo/anormalidades , Cerebelo/diagnóstico por imagem , Mapeamento Cromossômico , Cromossomos Humanos Par 4 , Cílios/genética , Estudos de Coortes , Consanguinidade , Éxons , Marcadores Genéticos , Haplótipos , Homozigoto , Humanos , Imuno-Histoquímica , Doenças Renais Císticas/genética , Masculino , Repetições de Microssatélites , Hipotonia Muscular/genética , Proteínas de Neoplasias/genética , Transtornos da Motilidade Ocular/genética , Linhagem , Polimorfismo de Nucleotídeo Único , Radiografia , Proteínas Recombinantes/metabolismo , Análise de Sequência de DNA , Síndrome , Técnicas do Sistema de Duplo-Híbrido
20.
Am J Hum Genet ; 75(5): 801-6, 2004 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-15368195

RESUMO

Weill-Marchesani syndrome (WMS) is characterized by the association of short stature; brachydactyly; joint stiffness; eye anomalies, including microspherophakia and ectopia of the lenses; and, occasionally, heart defects. We have recently mapped a gene for the autosomal recessive form of WMS to chromosome 19p13.3-p13.2, in a 12.4-cM interval. Here, we report null mutations in a member of the extracellular matrix protease family, the gene encoding ADAMTS10, a disintegrin and metalloprotease with thrombospondin motifs. A total of three distinct mutations were identified in two consanguineous families and in one sporadic WMS case, including one nonsense mutation (R237X) and two splice mutations (1190+1G-->A and 810+1G-->A). ADAMTS10 expression studies using reverse-transcriptase polymerase chain reaction, northern blot, and dot-blot analyses showed that ADAMTS10 is expressed in skin, fetal chondrocytes, and fetal and adult heart. Moreover, electron microscopy and immunological studies of the skin fibroblasts from the patients confirmed impairment of the extracellular matrix. We conclude, therefore, that ADAMTS10 plays a major role in growth and in skin, lens, and heart development in humans.


Assuntos
Anormalidades Múltiplas/genética , Proteínas da Matriz Extracelular/genética , Expressão Gênica , Proteínas ADAM , Proteínas ADAMTS , Actinas/metabolismo , Sequência de Bases , Northern Blotting , Criança , Primers do DNA , Nanismo/genética , Anormalidades do Olho/genética , Fibroblastos/imunologia , Fibroblastos/ultraestrutura , Componentes do Gene , Genes Recessivos/genética , Humanos , Immunoblotting , Metaloendopeptidases/genética , Microscopia Eletrônica , Dados de Sequência Molecular , Mutação/genética , Linhagem , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Análise de Sequência de DNA , Síndrome
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