RESUMEN
A small but growing body of scientific literature is emerging about clinical findings in patients with 19p13.3 microdeletion or duplication. Recently, a proximal 19p13.3 microduplication syndrome was described, associated with growth delay, microcephaly, psychomotor delay and dysmorphic features. The aim of our study was to better characterize the syndrome associated with duplications in the proximal 19p13.3 region (prox 19p13.3 dup), and to propose a comprehensive analysis of the underlying genomic mechanism. We report the largest cohort of patients with prox 19p13.3 dup through a collaborative study. We collected 24 new patients with terminal or interstitial 19p13.3 duplication characterized by array-based Comparative Genomic Hybridization (aCGH). We performed mapping, phenotype-genotype correlations analysis, critical region delineation and explored three-dimensional chromatin interactions by analyzing Topologically Associating Domains (TADs). We define a new 377 kb critical region (CR 1) in chr19: 3,116,922-3,494,377, GRCh37, different from the previously described critical region (CR 2). The new 377 kb CR 1 includes a TAD boundary and two enhancers whose common target is PIAS4. We hypothesize that duplications of CR 1 are responsible for tridimensional structural abnormalities by TAD disruption and misregulation of genes essentials for the control of head circumference during development, by breaking down the interactions between enhancers and the corresponding targeted gene.
Asunto(s)
Anomalías Múltiples , Microcefalia , Humanos , Hibridación Genómica Comparativa , Anomalías Múltiples/genética , Microcefalia/genética , Síndrome , Estudios de Asociación GenéticaRESUMEN
Xeroderma pigmentosum (XP) is a rare, genetic, autosomal nucleotide excision repair-deficient disease characterized by sun-sensitivity and early appearance of skin and ocular tumors. Thirty-two black-skinned XP from Comoros, located in the Indian Ocean, were counted, rendering this area the highest world prevalence of XP. These patients exhibited a new homozygous XPC mutation at the 3'-end of the intron12 (IVS 12-1G>C) leading to the absence of XPC protein. This mutation, characteristic of the consanguineous Comorian families, is associated with a founder effect with an estimated age of about 800 years. Analysis of mt-DNA and Y-chromosome identified the haplogroups of patients, who are derived from the Bantu people. Although the four Comorian islands were populated by the same individuals during the 7-10th centuries, XP was found now only in the Comorian island of Anjouan. To avoid the slavery process caused by the arrival of the Arabs around the 11-13th centuries, inhabitants of Anjouan, including XP-heterozygotes, hid inland of the island protected by volcanoes. This population lived with an endogamic style, without connection with the other islands. XP patients still live in the same isolated villages as their ancestries. Local history and geography may, thus, explain the high incidence of XP located exclusively in one island.
RESUMEN
Reunion Island is a French oversea department in the Indian Ocean with 1.6/1000, an estimated prevalence of deafness that is almost double as compared to the mainland France. Twelve children having isolated bilateral prelingual profound deafness along with motor delay attributed to vestibular areflexia were enrolled. Their mean walking age was 19 months. Electroretinography and temporal bone CT-scans were normal in all cases. A novel homozygous frameshift lipoma HMGIC fusion partner-like 5 (LHFPL5) variant c.185delT p.(Phe62Serfs*23) was identified using whole-exome sequencing. It was found in seven families. Four patients from two different families from both Reunion Island and mainland France, were compound heterozygous: c.185delT p.(Phe62Serfs*23) and c.472C > T p.(Arg158Trp). The phenotype observed in our patients completely mimics the hurry-scurry (hscy) murine Tmhs knock-out model. The recurrent occurrence of same LHFPL5 variant in Reunion Island is attributed to common ancestor couple born in 1693.
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Vestibulopatía Bilateral/genética , Sordera/genética , Proteínas de la Membrana/genética , Trastornos Motores/genética , Animales , Vestibulopatía Bilateral/diagnóstico por imagen , Vestibulopatía Bilateral/fisiopatología , Sordera/diagnóstico por imagen , Sordera/fisiopatología , Electrorretinografía , Femenino , Mutación del Sistema de Lectura/genética , Homocigoto , Humanos , Lactante , Masculino , Ratones , Trastornos Motores/diagnóstico por imagen , Trastornos Motores/fisiopatología , Linaje , Tomografía Computarizada por Rayos X , Secuenciación del ExomaRESUMEN
Although 22q11.2 deletion syndrome (22q11.2DS) is the most recurrent human microdeletion syndrome associated with a highly variable phenotype, little is known about the condition's true incidence and the phenotype at diagnosis. We performed a multicenter, retrospective analysis of postnatally diagnosed patients recruited by members of the Association des Cytogénéticiens de Langue Française (the French-Speaking Cytogeneticists Association). Clinical and cytogenetic data on 749 cases diagnosed between 1995 and 2013 were collected by 31 French cytogenetics laboratories. The most frequent reasons for referral of postnatally diagnosed cases were a congenital heart defect (CHD, 48.6%), facial dysmorphism (49.7%) and developmental delay (40.7%). Since 2007 (the year in which array comparative genomic hybridization (aCGH) was introduced for the routine screening of patients with intellectual disability), almost all cases have been diagnosed using FISH (96.1%). Only 15 cases (all with an atypical phenotype) were diagnosed with aCGH; the deletion size ranged from 745 to 2904 kb. The deletion was inherited in 15.0% of cases and was of maternal origin in 85.5% of the latter. This is the largest yet documented cohort of patients with 22q11.2DS (the most commonly diagnosed microdeletion) from the same population. French cytogenetics laboratories diagnosed at least 108 affected patients (including fetuses) per year from among a national population of â¼66 million. As observed for prenatal diagnoses, CHDs were the most frequently detected malformation in postnatal diagnoses. The most common CHD in postnatal diagnoses was an isolated septal defect.
Asunto(s)
Síndrome de Deleción 22q11/diagnóstico , Pruebas Genéticas/estadística & datos numéricos , Síndrome de Deleción 22q11/epidemiología , Síndrome de Deleción 22q11/genética , Adolescente , Adulto , Niño , Preescolar , Hibridación Genómica Comparativa , Femenino , Francia , Pruebas Genéticas/métodos , Humanos , Hibridación Fluorescente in Situ , Lactante , Recién Nacido , Masculino , Herencia PaternaRESUMEN
Heterozygous COL2A1 variants cause a wide spectrum of skeletal dysplasia termed type II collagenopathies. We assessed the impact of this gene in our French series. A decision tree was applied to select 136 probands (71 Stickler cases, 21 Spondyloepiphyseal dysplasia congenita cases, 11 Kniest dysplasia cases, and 34 other dysplasia cases) before molecular diagnosis by Sanger sequencing. We identified 66 different variants among the 71 positive patients. Among those patients, 18 belonged to multiplex families and 53 were sporadic. Most variants (38/44, 86%) were located in the triple helical domain of the collagen chain and glycine substitutions were mainly observed in severe phenotypes, whereas arginine to cysteine changes were more often encountered in moderate phenotypes. This series of skeletal dysplasia is one of the largest reported so far, adding 44 novel variants (15%) to published data. We have confirmed that about half of our Stickler patients (46%) carried a COL2A1 variant, and that the molecular spectrum was different across the phenotypes. To further address the question of genotype-phenotype correlation, we plan to screen our patients for other candidate genes using a targeted next-generation sequencing approach.
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Sustitución de Aminoácidos , Artritis/genética , Enfermedades del Colágeno/genética , Colágeno Tipo II/genética , Enfermedades del Tejido Conjuntivo/genética , Pérdida Auditiva Sensorineural/genética , Osteocondrodisplasias/genética , Fenotipo , Desprendimiento de Retina/genética , Artritis/patología , Enfermedades del Colágeno/patología , Colágeno Tipo II/química , Enfermedades del Tejido Conjuntivo/patología , Femenino , Pérdida Auditiva Sensorineural/patología , Humanos , Masculino , Osteocondrodisplasias/patología , Linaje , Dominios Proteicos , Desprendimiento de Retina/patologíaRESUMEN
Methionyl-tRNA synthetase (MARS) catalyzes the ligation of methionine to tRNA and is critical for protein biosynthesis. We identified biallelic missense mutations in MARS in a specific form of pediatric pulmonary alveolar proteinosis (PAP), a severe lung disorder that is prevalent on the island of Réunion and the molecular basis of which is unresolved. Mutations were found in 26 individuals from Réunion and nearby islands and in two families from other countries. Functional consequences of the mutated alleles were assessed by growth of wild-type and mutant strains and methionine-incorporation assays in yeast. Enzyme activity was attenuated in a liquid medium without methionine but could be restored by methionine supplementation. In summary, identification of a founder mutation in MARS led to the molecular definition of a specific type of PAP and will enable carrier screening in the affected community and possibly open new treatment opportunities.
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Metionina-ARNt Ligasa/genética , Proteinosis Alveolar Pulmonar/genética , Adolescente , Alelos , Niño , Preescolar , Retículo Endoplásmico/genética , Retículo Endoplásmico/patología , Femenino , Aparato de Golgi/genética , Aparato de Golgi/patología , Humanos , Masculino , Mutación Missense , Biosíntesis de Proteínas , Proteinosis Alveolar Pulmonar/patología , Adulto JovenRESUMEN
Most patients with Ellis-van Creveld syndrome (EvC) are identified with pathogenic changes in EVC or EVC2, however further genetic heterogeneity has been suggested. In this report we describe pathogenic splicing variants in WDR35, encoding retrograde intraflagellar transport protein 121 (IFT121), in three families with a clinical diagnosis of EvC but having a distinctive phenotype. To understand why WDR35 variants result in EvC, we analysed EVC, EVC2 and Smoothened (SMO) in IFT-A deficient cells. We found that the three proteins failed to localize to Wdr35(-/-) cilia, but not to the cilium of the IFT retrograde motor mutant Dync2h1(-/-), indicating that IFT121 is specifically required for their entry into the ciliary compartment. Furthermore expression of Wdr35 disease cDNAs in Wdr35(-/-) fibroblasts revealed that the newly identified variants lead to Hedgehog signalling defects resembling those of Evc(-/-) and Evc2(-/-) mutants. Together our data indicate that splicing variants in WDR35, and possibly in other IFT-A components, underlie a number of EvC cases by disrupting targeting of both the EvC complex and SMO to cilia.
Asunto(s)
Cilios/metabolismo , Síndrome de Ellis-Van Creveld/genética , Proteínas/genética , Receptores Acoplados a Proteínas G/genética , Células Cultivadas , Preescolar , Proteínas del Citoesqueleto , Exoma , Exones , Fibroblastos/metabolismo , Variación Genética , Proteínas Hedgehog , Humanos , Lactante , Péptidos y Proteínas de Señalización Intracelular , Linaje , Fenotipo , Proteínas/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Transducción de Señal , Receptor SmoothenedRESUMEN
Fetal edema can present as limited subcutaneous edema, fluid accumulation in body cavities or hydrops fetalis. Hydrops fetalis is the end stage of a variety of fetal/maternal disorders and nonimmune etiology represents more than 3/4 of cases. Lymphatic dysplasia may account for a subset of patients with nonimmune and "idiopathic" hydrops fetalis, fetal chylous ascites or chylothorax. We present two unrelated patients with antenatal features of hereditary lymphedema syndrome, in whom Milroy disease was diagnosed after birth. At least, 20 genes have been identified to cause primary lymphedema, with sometimes antenatal features. Hereditary lymphedema syndrome should be considered in cases of nonimmune hydrops fetalis/fetal edema after ruling out the more common etiologies.
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Hidropesía Fetal/diagnóstico por imagen , Linfedema/diagnóstico por imagen , Receptor 3 de Factores de Crecimiento Endotelial Vascular/genética , Adulto , Femenino , Humanos , Hidropesía Fetal/genética , Recién Nacido , Linfedema/genética , Masculino , Mutación Missense , Embarazo , Ultrasonografía PrenatalRESUMEN
First described as a variant of Larsen syndrome in Reunion Island (LRS) in the southern Indian Ocean, 'Larsen of Reunion Island syndrome' is characterized by dwarfism, hyperlaxity, multiple dislocations and distinctive facial features. It overlaps with Desbuquois dysplasia, Larsen syndrome and spondyloepiphyseal dysplasia with dislocations ascribed to CANT1, FLNB and CHST3 mutations, respectively. We collected the samples of 22 LRS cases. After exclusion of CANT1, FLNB and CHST3 genes, an exome sequencing was performed in two affected second cousins and one unaffected sister. We identified a homozygous missense mutation in B4GALT7, NM_007255.2: c.808C>T p.(Arg270Cys) named p.R270C, in the two affected cases, not present in the unaffected sister. The same homozygous mutation was subsequently identified in the remaining 20 LRS cases. Our findings demonstrate that B4GALT7 is the causative gene for LRS. The identification of a unique homozygous mutation argues in favor of a founder effect. B4GALT7 encodes a galactosyltransferase, required for the initiation of glycoaminoglycan side chain synthesis of proteoglycans. This study expands the phenotypic spectrum of B4GALT7 mutations, initially described as responsible for the progeroid variant of Ehlers-Danlos syndrome. It further supports a common physiopathological basis involving proteoglycan synthesis in skeletal disorders with dislocations.
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Efecto Fundador , Galactosiltransferasas/deficiencia , Galactosiltransferasas/genética , Homocigoto , Mutación , Adolescente , Adulto , Niño , Facies , Femenino , Fluorenos , Frecuencia de los Genes , Humanos , Hidantoínas , Masculino , Persona de Mediana Edad , Osteocondrodisplasias/diagnóstico , Osteocondrodisplasias/genética , Linaje , Fenotipo , Análisis de Secuencia de ADN , Adulto JovenRESUMEN
Relevant for various areas of human genetics, Y-chromosomal short tandem repeats (Y-STRs) are commonly used for testing close paternal relationships among individuals and populations, and for male lineage identification. However, even the widely used 17-loci Yfiler set cannot resolve individuals and populations completely. Here, 52 centers generated quality-controlled data of 13 rapidly mutating (RM) Y-STRs in 14,644 related and unrelated males from 111 worldwide populations. Strikingly, >99% of the 12,272 unrelated males were completely individualized. Haplotype diversity was extremely high (global: 0.9999985, regional: 0.99836-0.9999988). Haplotype sharing between populations was almost absent except for six (0.05%) of the 12,156 haplotypes. Haplotype sharing within populations was generally rare (0.8% nonunique haplotypes), significantly lower in urban (0.9%) than rural (2.1%) and highest in endogamous groups (14.3%). Analysis of molecular variance revealed 99.98% of variation within populations, 0.018% among populations within groups, and 0.002% among groups. Of the 2,372 newly and 156 previously typed male relative pairs, 29% were differentiated including 27% of the 2,378 father-son pairs. Relative to Yfiler, haplotype diversity was increased in 86% of the populations tested and overall male relative differentiation was raised by 23.5%. Our study demonstrates the value of RM Y-STRs in identifying and separating unrelated and related males and provides a reference database.
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Cromosomas Humanos Y/química , Dermatoglifia del ADN/métodos , Genética de Población , Haplotipos , Repeticiones de Microsatélite , África , Alelos , Américas , Asia , Dermatoglifia del ADN/estadística & datos numéricos , Europa (Continente) , Frecuencia de los Genes , Variación Genética , Humanos , Masculino , Paternidad , Linaje , Población Rural , Población UrbanaRESUMEN
Hemochromatosis type 4 is a rare form of primary iron overload transmitted as an autosomal dominant trait caused by mutations in the gene encoding the iron transport protein ferroportin 1 (SLC40A1). SLC40A1 mutations fall into two functional categories (loss- versus gain-of-function) underlying two distinct clinical entities (hemochromatosis type 4A versus type 4B). However, the vast majority of SLC40A1 mutations are rare missense variations, with only a few showing strong evidence of causality. The present study reports the results of an integrated approach collecting genetic and phenotypic data from 44 suspected hemochromatosis type 4 patients, with comprehensive structural and functional annotations. Causality was demonstrated for 10 missense variants, showing a clear dichotomy between the two hemochromatosis type 4 subtypes. Two subgroups of loss-of-function mutations were distinguished: one impairing cell-surface expression and one altering only iron egress. Additionally, a new gain-of-function mutation was identified, and the degradation of ferroportin on hepcidin binding was shown to probably depend on the integrity of a large extracellular loop outside of the hepcidin-binding domain. Eight further missense variations, on the other hand, were shown to have no discernible effects at either protein or RNA level; these were found in apparently isolated patients and were associated with a less severe phenotype. The present findings illustrate the importance of combining in silico and biochemical approaches to fully distinguish pathogenic SLC40A1 mutations from benign variants. This has profound implications for patient management.
Asunto(s)
Proteínas de Transporte de Catión/deficiencia , Hemocromatosis/genética , Anotación de Secuencia Molecular , Mutación Missense/genética , Adulto , Anciano , Sustitución de Aminoácidos/genética , Transporte Biológico , Proteínas de Transporte de Catión/sangre , Proteínas de Transporte de Catión/genética , Simulación por Computador , Femenino , Ferritinas/sangre , Frecuencia de los Genes/genética , Estudios de Asociación Genética , Células HEK293 , Hemocromatosis/sangre , Hepcidinas/farmacología , Humanos , Espacio Intracelular/metabolismo , Hierro/metabolismo , Masculino , Persona de Mediana Edad , Modelos Moleculares , Empalme del ARN/genética , Relación Estructura-Actividad , Población Blanca/genética , Adulto JovenRESUMEN
Creatine and guanidinoacetate are biomarkers of creatine metabolism. Their assays in body fluids may be used for detecting patients with primary creatine deficiency disorders (PCDD), a class of inherited diseases. Their laboratory values in blood and urine may vary with age, requiring that reference normal values are given within the age range. Despite the long known role of creatine for muscle physiology, muscle signs are not necessarily the major complaint expressed by PCDD patients. These disorders drastically affect brain function inducing, in patients, intellectual disability, autistic behavior and other neurological signs (delays in speech and language, epilepsy, ataxia, dystonia and choreoathetosis), being a common feature the drop in brain creatine content. For this reason, screening of PCDD patients has been repeatedly carried out in populations with neurological signs. This report is aimed at providing reference laboratory values and related age ranges found for a large scale population of patients with neurological signs (more than 6 thousand patients) previously serving as a background population for screening French patients with PCDD. These reference laboratory values and age ranges compare rather favorably with literature values for healthy populations. Some differences are also observed, and female participants are discriminated from male participants as regards to urine but not blood values including creatine on creatinine ratio and guanidinoacetate on creatinine ratio values. Such gender differences were previously observed in healthy populations; they might be explained by literature differential effects of testosterone and estrogen in adolescents and adults, and by estrogen effects in prepubertal age on SLC6A8 function. Finally, though they were acquired on a population with neurological signs, the present data might reasonably serve as reference laboratory values in any future medical study exploring abnormalities of creatine metabolism and transport.
Asunto(s)
Creatina/metabolismo , Glicina/análogos & derivados , Población Blanca , Adolescente , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Errores Innatos del Metabolismo de los Aminoácidos/diagnóstico , Errores Innatos del Metabolismo de los Aminoácidos/metabolismo , Estudios de Casos y Controles , Niño , Preescolar , Creatina/sangre , Creatina/orina , Femenino , Francia , Glicina/sangre , Glicina/metabolismo , Glicina/orina , Humanos , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Valores de Referencia , Factores Sexuales , Adulto JovenRESUMEN
Friedreich's ataxia (FRDA) is a severe neurodegenerative disease caused by GAA repeat expansion within the first intron of the frataxin gene. It has been suggested that the repeat is responsible for the disease severity due to impaired transcription thereby reducing expression of the protein. However, genotype-phenotype correlation is imperfect, and the influence of other gene regions of the frataxin gene is unknown. We hypothesized that FRDA patients may harbor specific regulatory variants in the 3'-UTR. We sequenced the 3'-UTR region of the frataxin gene in a cohort of 57 FRDA individuals and 58 controls. Seven single nucleotide polymorphisms (SNPs) out of 19 were polymorphic in our case-control sample. These SNPs defined several haplotypes with one reaching 89% of homozygosity in patients versus 24% in controls. In another cohort of 47 FRDA Reunionese patients, 94% patients were found to be homozygous for this haplotype. We found that this FRDA 3'-UTR conferred a 1.2-fold decrease in the expression of a reporter gene versus the alternative haplotype configuration. We established that differential targeting by miRNA could account for this functional variability. We specifically demonstrated the involvement of miR-124 (i.e hsa-mir-124-3p) in the down-regulation of FRDA-3'-UTR. Our results suggest for the first time that post-transcriptional regulation of frataxin occurs through the 3'-UTR and involves miRNA targeting. We propose that the involvement of miRNAs in a FRDA-specific regulation of frataxin may provide a rationale to increase residual levels of frataxin through miRNA-inhibitory molecules.
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Regiones no Traducidas 3' , Ataxia de Friedreich/genética , Regulación de la Expresión Génica , Variación Genética , Proteínas de Unión a Hierro/genética , MicroARNs/genética , Secuencia de Bases , Estudios de Casos y Controles , Línea Celular , Biología Computacional/métodos , Frecuencia de los Genes , Orden Génico , Predisposición Genética a la Enfermedad , Haplotipos , Humanos , MicroARNs/metabolismo , Polimorfismo de Nucleótido Simple , Expansión de Repetición de Trinucleótido , FrataxinaRESUMEN
A population of patients with unexplained neurological symptoms from six major French university hospitals was screened over a 28-month period for primary creatine disorder (PCD). Urine guanidinoacetate (GAA) and creatine:creatinine ratios were measured in a cohort of 6,353 subjects to identify PCD patients and compile their clinical, 1H-MRS, biochemical and molecular data. Six GAMT [N-guanidinoacetatemethyltransferase (EC 2.1.1.2)] and 10 X-linked creatine transporter (SLC6A8) but no AGAT (GATM) [L-arginine/glycine amidinotransferase (EC 2.1.4.1)] deficient patients were identified in this manner. Three additional affected sibs were further identified after familial inquiry (1 brother with GAMT deficiency and 2 brothers with SLC6A8 deficiency in two different families). The prevalence of PCD in this population was 0.25% (0.09% and 0.16% for GAMT and SLC6A8 deficiencies, respectively). Seven new PCD-causing mutations were discovered (2 nonsense [c.577C > T and c.289C > T] and 1 splicing [c.391 + 15G > T] mutations for the GAMT gene and, 2 missense [c.1208C > A and c.926C > A], 1 frameshift [c.930delG] and 1 splicing [c.1393-1G > A] mutations for the SLC6A8 gene). No hot spot mutations were observed in these genes, as all the mutations were distributed throughout the entire gene sequences and were essentially patient/family specific. Approximately one fifth of the mutations of SLC6A8, but not GAMT, were attributed to neo-mutation, germinal or somatic mosaicism events. The only SLC6A8-deficient female patient in our series presented with the severe phenotype usually characterizing affected male patients, an observation in agreement with recent evidence that is in support of the fact that this X-linked disorder might be more frequent than expected in the female population with intellectual disability.
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Creatina/deficiencia , Creatina/orina , Enfermedades del Sistema Nervioso/etiología , Creatinina/orina , Femenino , Glicina/análogos & derivados , Glicina/orina , Humanos , Masculino , Proteínas del Tejido Nervioso/genética , Enfermedades del Sistema Nervioso/orina , Proteínas de Transporte de Neurotransmisores en la Membrana Plasmática/genética , Estudios RetrospectivosRESUMEN
The human genome is densely populated with transposons and transposon-like repetitive elements. Although the impact of these transposons and elements on human genome evolution is recognized, the significance of subtle variations in their sequence remains mostly unexplored. Here we report homozygosity mapping of an infantile neurodegenerative disease locus in a genetic isolate. Complete DNA sequencing of the 400-kb linkage locus revealed a point mutation in a primate-specific retrotransposon that was transcribed as part of a unique noncoding RNA, which was expressed in the brain. In vitro knockdown of this RNA increased neuronal apoptosis, consistent with the inappropriate dosage of this RNA in vivo and with the phenotype. Moreover, structural analysis of the sequence revealed a small RNA-like hairpin that was consistent with the putative gain of a functional site when mutated. We show here that a mutation in a unique transposable element-containing RNA is associated with lethal encephalopathy, and we suggest that RNAs that harbor evolutionarily recent repetitive elements may play important roles in human brain development.
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Encefalopatías/genética , Secuencia Conservada/genética , Mutación/genética , Primates/genética , ARN no Traducido/genética , Retroelementos/genética , Animales , Anorexia/complicaciones , Anorexia/genética , Secuencia de Bases , Encefalopatías/complicaciones , Encefalopatías/patología , Mapeo Cromosómico , Segregación Cromosómica/genética , Cromosomas Humanos Par 8/genética , Progresión de la Enfermedad , Genes Recesivos/genética , Sitios Genéticos , Geografía , Humanos , Océano Índico , Lactante , Intrones/genética , Imagen por Resonancia Magnética , Datos de Secuencia Molecular , Conformación de Ácido Nucleico , Nucleótidos/genética , Fenotipo , ARN no Traducido/química , Adulto JovenRESUMEN
Autosomal recessive renal tubular dysgenesis (RTD) is a severe disorder of renal tubular development characterized by early onset and persistent fetal anuria leading to oligohydramnios and the Potter sequence, associated with skull ossification defects. Early death occurs in most cases from anuria, pulmonary hypoplasia, and refractory arterial hypotension. The disease is linked to mutations in the genes encoding several components of the renin-angiotensin system (RAS): AGT (angiotensinogen), REN (renin), ACE (angiotensin-converting enzyme), and AGTR1 (angiotensin II receptor type 1). Here, we review the series of 54 distinct mutations identified in 48 unrelated families. Most of them are novel and ACE mutations are the most frequent, observed in two-thirds of families (64.6%). The severity of the clinical course was similar whatever the mutated gene, which underlines the importance of a functional RAS in the maintenance of blood pressure and renal blood flow during the life of a human fetus. Renal hypoperfusion, whether genetic or secondary to a variety of diseases, precludes the normal development/ differentiation of proximal tubules. The identification of the disease on the basis of precise clinical and histological analyses and the characterization of the genetic defects allow genetic counseling and early prenatal diagnosis.
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Genes Recesivos , Mutación , Sistema Renina-Angiotensina/genética , Anomalías Urogenitales/genética , Angiotensinógeno/genética , Animales , Modelos Animales de Enfermedad , Estudios de Asociación Genética , Humanos , Túbulos Renales Proximales/anomalías , Peptidil-Dipeptidasa A/genética , Receptor de Angiotensina Tipo 1/genética , Renina/genética , Anomalías Urogenitales/diagnósticoRESUMEN
Xeroderma pigmentosum (XP) is a rare, recessive disease characterized by sunlight hypersensitivity and early appearance of cutaneous and ocular malignancies. We report the first description of a very high incidence (around 1/5000) of black XP patients in the Mayotte population in the Indian Ocean. Among a cohort of 32 XP, we describe the clinical and genetic features of 18 living Comorian black XP patients. We discuss the remarkable clinical differences between white and black XPs. Skin and ocular abnormalities are remarkably precocious and severe XP phenotypes are recognized by the early ocular injuries. In our cohort, the first skin cancer appeared at a median age of 4.5 years with no neurological symptoms. Post-UV DNA repair, cell survival and genetic complementation assigned these patients to the XP group C. All patients exhibited a new GâC homozygous substitution at 3'-end of XPC intron 12 (IVS 12-1G>C) leading to the abolition of an acceptor splicing site and the absence of the XPC protein. We found 3 different mRNA isoforms: one with retention of intron 12, one showing exon 13 skipping, and a third with a 44bp deletion in exon 13. These 3 isoforms were differently expressed in XP-C cells compared to normal cells. This new mutation found in the Comorian islands, where consanguinity is frequent, represents a founder effect, with an estimated age of about 770 years. Due to the African origin of the black XPs from Mayotte, it would be valuable to search for this mutation in African XPs whenever possible.
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Empalme Alternativo , Proteínas de Unión al ADN/genética , Mutación , Xerodermia Pigmentosa/genética , Adolescente , Adulto , Secuencia de Bases , Niño , Preescolar , Comoras/epidemiología , Femenino , Humanos , Lactante , Intrones , Masculino , Datos de Secuencia Molecular , ARN Mensajero/genética , Xerodermia Pigmentosa/epidemiología , Adulto JovenAsunto(s)
Cromosomas Humanos Par 22 , Asesoramiento Genético , Mosaicismo , Trisomía , Adulto , Femenino , Humanos , Embarazo , Diagnóstico PrenatalAsunto(s)
Conductos Biliares/anomalías , Enfermedades Óseas/complicaciones , Cilios/patología , Fémur/anomalías , Enfermedades Renales Quísticas/complicaciones , Enfermedades Renales Quísticas/patología , Hermanos , Situs Inversus/complicaciones , Adulto , Enfermedades Óseas/congénito , Análisis Mutacional de ADN , Resultado Fatal , Femenino , Fémur/diagnóstico por imagen , Humanos , Cinesinas/genética , Masculino , Embarazo , Radiografía , Reunión , Situs Inversus/patologíaRESUMEN
Reunion Island is a French territory located in the western Indian Ocean. The genetic pattern of the Reunionese population has been shaped by contributions from highly contrasting regions of the world. Over the last 350 years, several migration waves and cultural and socio-economic factors have led to the emergence of six main ethnic groups in Reunion. India is one of the principal regions that contributed to the setting up of the Reunionese population. Diversity, demographic and admixture analyses were performed on mtDNA variation of the Reunionese of Indian ancestry, including the Malbar and Zarab ethnic groups, in order to question their history. Using a phylogeographical approach, we generated and analysed quantitative data on the contribution of the Indian parental populations. Furthermore, we showed that the settlement of Reunion Island by Indians did not involve a founder effect, except in the very beginning of the Reunionese settlement (at the end of the 17(th) century). The accuracy of our results was optimised by a re-evaluation of the classification of the Southern Asian mtDNA haplogroups. Finally, by comparing our results to a previous study dealing with the Reunionese population, we highlighted how ethno-historical data are critical for reconstructing the complex history of multiethnic populations.