RESUMEN
We describe a previously unreported syndrome characterized by secondary (post-natal) microcephaly with fronto-temporal lobe hypoplasia, multiple pituitary hormone deficiency, seizures, severe visual impairment and abnormalities of the kidneys and urinary tract in a highly consanguineous family with six affected children. Homozygosity mapping and exome sequencing revealed a novel homozygous frameshift mutation in the basic helix-loop-helix transcription factor gene ARNT2 (c.1373_1374dupTC) in affected individuals. This mutation results in absence of detectable levels of ARNT2 transcript and protein from patient fibroblasts compared with controls, consistent with nonsense-mediated decay of the mutant transcript and loss of ARNT2 function. We also show expression of ARNT2 within the central nervous system, including the hypothalamus, as well as the renal tract during human embryonic development. The progressive neurological abnormalities, congenital hypopituitarism and post-retinal visual pathway dysfunction in affected individuals demonstrates for the first time the essential role of ARNT2 in the development of the hypothalamo-pituitary axis, post-natal brain growth, and visual and renal function in humans.
Asunto(s)
Translocador Nuclear del Receptor de Aril Hidrocarburo/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Hipopituitarismo/genética , Riñón/anomalías , Microcefalia/genética , Mutación/genética , Hormonas Hipofisarias/metabolismo , Percepción Visual , Niño , Preescolar , Femenino , Humanos , Hipopituitarismo/diagnóstico , Hipotálamo/metabolismo , Riñón/metabolismo , Masculino , Microcefalia/diagnóstico , Hormonas Hipofisarias/genética , Síndrome , Factores de TranscripciónRESUMEN
Next generation sequencing (NGS) is a promising technique that can reveal the entire gene sequences and to the highest possible resolution without any phase ambiguities. We have used this technique to investigate the frequencies of HLA-A, -B, -C, -DRB1 and -DQB1 in a Saudi cohort of healthy individuals. We used NGS using the 454 genome sequence (GS) FLX System and Conexio assign atf 454 software to human leukocyte antigen (HLA) genotype eight class I and class II loci. A total of 158 healthy Saudi adults were analyzed. The most frequently observed allele for HLA-A was HLA-A*02:01:01:01 (13.6%); for HLA-B, HLA-B*50:01:01 (15.8%); for HLA-C, HLA-C*06:02:01:01 (18.7%); for HLA-DRB1, HLA-DRB1*07:01:01:01 (26.6%); and for HLA-DQB1, HLA-DQB1*02:01:01 (20.3%). The most common four loci haplotypes in the Saudi population were HLA-A*24:02:01:01-B*08:01:01-C*07:02:01:01-DRB1*03:01:01:01 and HLA-A*23:01:01-B*50:01:01-C*06:02:01:01-DRB1*07:01:01:01.. We have used a highly informative technique for HLA typing of a Saudi healthy cohort to establish allele and haplotype frequencies. These results should prove useful for population studies, disease associations and future planning of the unrelated bone marrow donor registry.
Asunto(s)
Antígenos HLA-A/inmunología , Antígenos HLA-B/inmunología , Antígenos HLA-C/inmunología , Cadenas beta de HLA-DQ/inmunología , Cadenas HLA-DRB1/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Alelos , Femenino , Frecuencia de los Genes , Haplotipos , Secuenciación de Nucleótidos de Alto Rendimiento , Prueba de Histocompatibilidad , Humanos , Masculino , Persona de Mediana Edad , Arabia Saudita , Análisis de Secuencia de ADNRESUMEN
OBJECTIVE: Genome-Wide association studies (GWAS) showed an association between subset of single-nucleotide polymorphism (SNPs) and multiple sclerosis. Our study aims to study this association in Saudi familial multiple sclerosis patients. METHODS: Four subject groups were used in this study: sporadic MS (MS patients without family history), FMS (MS patients who have at least one family member diagnosed with MS), related controls (relatives of FMS patients who appear to be free of the disease) and independent controls (healthy volunteers). Subjects were genotyped for 15 SNPs. The variation in the genotype distribution was analyzed across study groups by using logistic regression. RESULTS: 342 subjects were included. 99 were in the sporadic MS group, 22 were FMS, 89 were related control, and 132 were independent control. SNPS rs3135388, rs7577363, rs1321172, rs6897932, rs6498169, rs12487066, and rs4763655were associated with MS when MS and independent control groups were compared. Same SNPS were identified but with stronger association when the FMS and independent control groups were compared. Finally, when the patients and the controls were selected from a much more homogenous genetic pool from which it would be expected that only SNPs highly linked to MS would persist, only two SNPs rs6498169[OR 4.26, CI (1.17 - 15.51)];, and rs10984447 [OR 13.63, CI(1.54, 120.83) ][were associated with MS. CONCLUSIONS: Our results suggest that using a more homogenous genetic pool of cases and controls could help to identify the most significant MS-associated SNPs. Our finding is in agreement with other studies including larger sample size and more diverse populations.
Asunto(s)
Ligamiento Genético , Predisposición Genética a la Enfermedad/genética , Estudio de Asociación del Genoma Completo/métodos , Esclerosis Múltiple/genética , Polimorfismo de Nucleótido Simple , Adulto , Femenino , Genotipo , Humanos , Masculino , Modelos Genéticos , Sistema de Registros , Proyectos de Investigación , Arabia SauditaRESUMEN
Several studies have investigated the association of different HLA antigens with multiple sclerosis (MS). However, only few studies have considered the association of high-resolution HLA type and MS with none yet from Saudi Arabia. The aim of this study was to investigate the association of HLA class II alleles with MS in the Saudi population. We used next-generation sequencing to investigate HLA association with MS. This study was conducted at King Abdulaziz Medical City in Riyadh, Saudi Arabia. We found that several HLA-DRB1 and DQB1 alleles were associated with MS. These alleles included HLA-DRB1*15:01 (odds ratio [OR]: 3.01; 95%, confidence interval [CI]: 1.68-5.54; P = .0001), HLA-DQB1*02:01 (OR: 1.76; 95% CI: 1.20-2.58; P = .0022), HLA-DQB1*06:02 (OR: 3.52; 95% CI: 1.87-6.86; P < .0001), and HLA-DQB1*06:03 (OR: 2.42; 95% CI: 1.16-5.25; P = 0.01). Interestingly, HLA-DRB1*15:01 was associated with increased risk of previous relapses. In addition, HLA-DRB1*15:01 and HLA-DQB1*06:02 were found to be associated with lower vitamin D levels. This study provides insights on the association of different HLA alleles with clinical characteristics and outcome of MS among Saudis. These insights can have future implications for the clinical management of MS based on the patient genetic profile.
Asunto(s)
Alelos , Cadenas beta de HLA-DQ/genética , Cadenas HLA-DRB1/genética , Esclerosis Múltiple/genética , Polimorfismo Genético , Adulto , Femenino , Cadenas beta de HLA-DQ/inmunología , Cadenas HLA-DRB1/inmunología , Humanos , Masculino , Esclerosis Múltiple/epidemiología , Esclerosis Múltiple/inmunología , Factores de Riesgo , Arabia SauditaRESUMEN
CCR5 is a chemokine receptor that was found to be used by HIV as a co-receptor for entering target cells. A 32 bp deletion was described in certain people that rendered CCR5 non-functional. The mutant allele CCR5-Δ32 has been shown to prevent HIV infection. In addition, stem cell transplantation with the CCR5-Δ32 homozygous genotype can lead to clearance of HIV infection. In this study, our aim was to investigate the frequency of CCR5-Δ32 mutation in a cohort of stem cell donors from cord blood bank and stem cell donor registry. A total of 3025 samples were collected from healthy stem cell donors (2625) and from cord blood units (400). DNA was extracted and the CCR5 gene was amplified by polymerase chain reaction (PCR) in a light cycler system using SYBR Green dye. The mutated gene was further confirmed by direct gene sequencing. We found 38 heterozygous for CCR5-Δ32 and one homozygous CCR5 mutation (Δ32/Δ32) out of the 3025 tested individuals. We conclude that the protective CCR5-Δ32 allele appears to be rarely present in Saudi Arabia.
Asunto(s)
Mutación/genética , Receptores CCR5/genética , Células Madre/metabolismo , Donantes de Tejidos , Secuencia de Bases , Frecuencia de los Genes/genética , Humanos , Prevalencia , Arabia SauditaRESUMEN
Congenital duplication of the palm is a rare syndrome with the following features: the dorsal aspects of both hands have thick palmar skin with no hair or nails; bilateral ulnar ray deficiency; short hypoplastic upper limbs; and severe lower limb abnormalities. In this paper, we report a new case of congenital duplication of the palm syndrome, provide its gene analysis identifying the responsible gene mutation in exon 4 of the WNT7a gene, and detail the molecular basis of its clinical features.