RESUMEN
Achondroplasia (ACH) is a frequent condition of unknown origin characterized by short-limbed dwarfism and macrocephaly. Milder forms, termed hypochondroplasias (HCH) result in short stature with radiological features similar to those observed in ACH. We report on the mapping of a gene causing ACH/HCH to human chromosome 4p16.3, by linkage to the iduronidase A (IDUA) locus, in 15 informative families (Z max = 3.01 at theta = 0 for ACH; Z max = 4.71 at theta = 0 for ACH/HCH). Multipoint linkage analysis provides evidence for mapping the disease locus telomeric to D4S412 (location score in log 10 = 4.60). Moreover, this study supports the view that ACH and HCH are genetically homogeneous in our series.
Asunto(s)
Acondroplasia/genética , Cromosomas Humanos Par 4 , Mapeo Cromosómico , Femenino , Genes Dominantes , Ligamiento Genético , Marcadores Genéticos , Humanos , Iduronidasa/genética , Masculino , LinajeRESUMEN
Holt-Oram syndrome (HOS) is an autosomal dominant condition of unknown origin characterized by congenital septal heart defects with associated malformations of the upper limbs (radial ray). Here, we report on the mapping of a gene causing HOS to the distal long arm of chromosome 12 (12q21-qter) by linkage analysis in nine informative families (Zmax = 6.81 at theta = 0 at the D12S354 locus). Also, multipoint linkage analysis places the HOS gene within the genetic interval between D12S84 and D12S79 (multipoint lod-score in log base 10 = 8.10). The mapping of a gene for HOS is, to our knowledge, the first chromosomal localization of a gene responsible for congenital septal heart defect in human. The characterization of the HOS gene will hopefully shed light on the molecular mechanisms that govern heart septation in the early stages of embryogenesis.
Asunto(s)
Anomalías Múltiples/genética , Brazo/anomalías , Cromosomas Humanos Par 12 , Genes Dominantes , Deformidades Congénitas de la Mano/genética , Cardiopatías Congénitas/genética , Mapeo Cromosómico , Ligamiento Genético , Humanos , Linaje , Recombinación Genética , SíndromeRESUMEN
Hirschsprung disease (HSCR) and Waardenburg sundrome (WS) are congenital malformations regarded as neurocristopathies since both disorders involve neural crest-derived cells. The WS-HSCR association (Shah-Waardenburg syndrome) is a rare autosomal recessive condition that occasionally has been ascribed to mutations of the endothelin-receptor B (EDNRB) gene. WS-HSCR mimicks the megacolon and white coat-spotting observed in Ednrb mouse mutants. Since mouse mutants for the EDNRB ligand, endothelin-3 (EDN3), displayed a similar phenotype, the EDN3 gene was regarded as an alternative candidate gene in WS-HSCR. Here, we report a homozygous substitution/deletion mutation of the EDN3 gene in a WS-HSCR patient. EDN3 thus becomes the third known gene (after RET and EDNRB) predisposing to HSCR, supporting the view that the endothelin-signaling pathways play a major role in the development of neural crests.
Asunto(s)
Endotelinas/genética , Enfermedad de Hirschsprung/complicaciones , Enfermedad de Hirschsprung/genética , Mutación , Síndrome de Waardenburg/complicaciones , Síndrome de Waardenburg/genética , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Preescolar , ADN/genética , Endotelinas/fisiología , Femenino , Genes Recesivos , Enfermedad de Hirschsprung/etiología , Homocigoto , Humanos , Masculino , Ratones , Datos de Secuencia Molecular , Cresta Neural/crecimiento & desarrollo , Fenotipo , Síndrome de Waardenburg/etiologíaRESUMEN
Hirschsprung disease (HSCR) is a frequent congenital disorder (1 in 5,000 newborns) of unknown origin characterized by the absence of parasympathetic intrinsic ganglion cells of the hindgut. Taking advantage of a proximal deletion of chromosome 10q (del 10q11.2-q21.2) in a patient with total colonic aganglionosis, and of a high-density genetic map of microsatellite DNA markers, we performed genetic linkage analysis in 15 non-syndromic long-segment and short-segment HSCR families. Multipoint linkage analysis indicated that the most likely location for a HSCR locus is between loci D10S208 and D10S196, suggesting that a dominant gene for HSCR maps to 10q11.2, a region to which other neural crest defects have been mapped.
Asunto(s)
Cromosomas Humanos Par 10 , Enfermedad de Hirschsprung/genética , Secuencia de Bases , Mapeo Cromosómico , ADN Satélite/genética , Familia , Femenino , Ligamiento Genético , Genotipo , Humanos , Recién Nacido , Masculino , Datos de Secuencia Molecular , Oligodesoxirribonucleótidos , Linaje , Reacción en Cadena de la Polimerasa/métodosRESUMEN
Hirschsprung disease (HSCR, aganglionic megacolon) is a common congenital malformation leading to bowel obstruction, with an incidence of 1/5,000 live births. It is characterized by the absence of intrinsic ganglion cells in the myenteric and submucosal plexuses along variable lengths of the gastrointestinal tract. As enteric neurons are derived from the vagal neural crest, HSCR is regarded as a neurocristopathy. On the basis of a skewed sex-ratio (M/F = 4/1) and a risk to relatives much higher than the incidence in the general population, HSCR has long been regarded as a sex-modified multifactorial disorder. Accordingly, segregation analysis suggested an incompletely penetrant dominant inheritance in HSCR families with aganglionosis extending beyond the sigmoid colon. We and others have mapped a dominant gene for HSCR to chromosome 10q11.2 and have ascribed the disease to mutations in the RET proto-oncogene. However, the lack of genotype-phenotype correlation, the low penetrance and the sex-dependent effect of RET mutations supported the existence of one or more modifier gene(s) in familial HSCR. In addition, thus far, RET mutations only accounted for 50% and 15-20% of familial and sporadic HSCR patients, respectively. RET encodes a tyrosine kinase receptor whose ligand was unknown. Recently, the Glial cell line-derived neurotrophic factor (GDNF) has been identified to be a ligand for RET. Moreover, Gdnf-/- knockout mutant mice display congenital intestinal aganglionosis and renal agenesis, a phenotype very similar to the Ret-/- mouse. These data prompted us to hypothesize that mutations of the gene encoding GDNF could either cause or modulate the HSCR phenotype in some cases.
Asunto(s)
Proteínas de Drosophila , Mutación de Línea Germinal , Enfermedad de Hirschsprung/genética , Factores de Crecimiento Nervioso , Proteínas del Tejido Nervioso/genética , Femenino , Factor Neurotrófico Derivado de la Línea Celular Glial , Receptores del Factor Neurotrófico Derivado de la Línea Celular Glial , Humanos , Masculino , Linaje , Fenotipo , Polimorfismo Conformacional Retorcido-Simple , Proto-Oncogenes Mas , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas c-ret , Proteínas Tirosina Quinasas Receptoras/genética , Análisis de Secuencia de ADNRESUMEN
Triple-A syndrome (MIM 231550; also known as Allgrove syndrome) is an autosomal recessive disorder characterized by adrenocorticotropin hormone (ACTH)-resistant adrenal insufficiency, achalasia of the oesophageal cardia and alacrima. Whereas several lines of evidence indicate that triple-A syndrome results from the abnormal development of the autonomic nervous system, late-onset progressive neurological symptoms (including cerebellar ataxia, peripheral neuropathy and mild dementia) suggest that the central nervous system may be involved in the disease as well. Using fine-mapping based on linkage disequilibrium in North African inbred families, we identified a short ancestral haplotype on chromosome 12q13 (<1 cM), sequenced a BAC contig encompassing the triple-A minimal region and identified a novel gene (AAAS) encoding a protein of 547 amino acids that is mutant in affected individuals. We found five homozygous truncating mutations in unrelated patients and ascribed the founder effect in North African families to a single splice-donor site mutation that occurred more than 2,400 years ago. The predicted product of AAAS, ALADIN (for alacrima-achalasia-adrenal insufficiency neurologic disorder), belongs to the WD-repeat family of regulatory proteins, indicating a new disease mechanism involved in triple-A syndrome. The expression of the gene in both neuroendocrine and cerebral structures points to a role in the normal development of the peripheral and central nervous systems.
Asunto(s)
Anomalías Múltiples/genética , Insuficiencia Suprarrenal/genética , Cromosomas Humanos Par 12/genética , Acalasia del Esófago/genética , Genes , Enfermedades del Sistema Nervioso/genética , Proteínas/genética , Xeroftalmia/genética , África del Norte , Secuencias de Aminoácidos , Secuencia de Aminoácidos , Cromosomas Artificiales Bacterianos/genética , Codón/genética , Consanguinidad , Análisis Mutacional de ADN , Evolución Molecular , Etiquetas de Secuencia Expresada , Haplotipos , Humanos , Desequilibrio de Ligamiento , Datos de Secuencia Molecular , Proteínas del Tejido Nervioso/química , Proteínas del Tejido Nervioso/deficiencia , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/fisiología , Proteínas de Complejo Poro Nuclear , Linaje , Mutación Puntual , Proteínas/química , Proteínas/fisiología , Secuencias Repetitivas de Aminoácido , Alineación de Secuencia , Homología de Secuencia de Aminoácido , Especificidad de la Especie , SíndromeRESUMEN
When illicit drugs are taken, men and women have a different biological response to drug used. Likewise, gender differences show more stigmas, more complex familial environment, and more history of sexual abuse for drug addicted women. The expression of psychiatric co-morbidities differs according to gender, with increased mood disorders, eating disorders, anxiety, and post traumatic disorders among drug addicted women.
Asunto(s)
Trastornos Relacionados con Sustancias/fisiopatología , Trastornos Relacionados con Sustancias/psicología , Femenino , Humanos , Masculino , Hombres/psicología , Trastornos Mentales/psicología , Factores Sexuales , Mujeres/psicologíaRESUMEN
Hirschsprung disease (HSCR, aganglionic megacolon) represents the main genetic cause of functional intestinal obstruction with an incidence of 1/5000 live births. This developmental disorder is a neurocristopathy and is characterised by the absence of the enteric ganglia along a variable length of the intestine. In the last decades, the development of surgical approaches has importantly decreased mortality and morbidity which allowed the emergence of familial cases. Isolated HSCR appears to be a non-Mendelian malformation with low, sex-dependent penetrance, and variable expression according to the length of the aganglionic segment. While all Mendelian modes of inheritance have been described in syndromic HSCR, isolated HSCR stands as a model for genetic disorders with complex patterns of inheritance. The tyrosine kinase receptor RET is the major gene with both rare coding sequence mutations and/or a frequent variant located in an enhancer element predisposing to the disease. Hitherto, 10 genes and five loci have been found to be involved in HSCR development.
Asunto(s)
Enfermedad de Hirschsprung/genética , Enfermedad de Hirschsprung/patología , Aberraciones Cromosómicas , Femenino , Enfermedad de Hirschsprung/epidemiología , Humanos , Obstrucción Intestinal/genética , Masculino , Biología Molecular , Mutación , Proteínas Tirosina Quinasas Receptoras/genética , SíndromeRESUMEN
The highlights 2008 in the addiction field are correlated to the progress of psychiatric neurosciences. Clarifications are also necessary towards the psychiatric comorbidities (schizophrenia) with the addictions. Then, useful considerations are given for the prescription of substitution treatment among HIV patients under tritherapy.
Asunto(s)
Psicología del Esquizofrénico , Trastornos Relacionados con Sustancias/psicología , Infecciones por VIH/complicaciones , Infecciones por VIH/psicología , HumanosRESUMEN
Currarino syndrome (CS) is a rare congenital malformation described in 1981 as the association of three main features: typical sacral malformation (sickle-shaped sacrum or total sacral agenesis below S2), hindgut anomaly, and presacral tumor. In addition to the triad, tethered cord and/or lipoma of the conus are also frequent and must be sought, as they may lead to severe complications if not treated. The HLXB9 gene, located at 7q36, is disease-causing. It encodes the HB9 transcription factor and interacts with DNA through a highly evolutionarily conserved homeodomain early in embryological development. Thus far, 43 different heterozygous mutations have been reported in patients fulfilling CS criteria. Mutation detection rate is about 50%, and reaches 90% in familial cases. Here, we report 23 novel mutations in 26 patients among a series of 50 index cases with CS, and review mutational reports published since the identification of the causative gene. Three cytogenetic anomalies encompassing the HLXB9 gene are described for the first time. Truncating mutations (frameshifts or nonsense mutations) represent 57% of those identified, suggesting that haploinsufficiency is the basis of CS. No obvious genotype-phenotype correlation can be drawn thus far. Genetic heterogeneity is suspected, since at least 19 of the 24 patients without HLXB9 gene mutation harbor subtle phenotypic variations.
Asunto(s)
Anomalías Múltiples/genética , Proteínas de Homeodominio/genética , Intestinos/anomalías , Sacro/anomalías , Factores de Transcripción/genética , Secuencia de Bases , Exones , Familia , Femenino , Genotipo , Proteínas de Homeodominio/fisiología , Humanos , Masculino , Mutación , Fenotipo , Síndrome , Factores de Transcripción/fisiologíaRESUMEN
Hirschsprung disease (HSCR) stands as a model for genetic dissection of complex diseases. In this model, a major gene, RET, is involved in most if not all cases of isolated (i.e., nonsyndromic) HSCR, in conjunction with other autosomal susceptibility loci under a multiplicative model. HSCR susceptibility alleles can harbor either heterozygous coding sequence mutations or, more frequently, a polymorphism within intron 1, leading to a hypomorphic RET allele. On the other hand, about 30% of HSCR are syndromic. Hitherto, the disease causing gene has been identified for eight Mendelian syndromes with HSCR: congenital central hypoventilation (CCHS), Mowat-Wilson (MWS), Bardet-Biedl (BBS), Shah-Waardenburg (WS4), cartilage-hair-hypoplasia (CHH), Smith-Lemli-Opitz (SLO), Goldberg-Sprintzsen (GSS), and hydrocephalus due to congenital stenosis of the aqueduct of sylvius (HSAS). According to the HSCR syndrome, the penetrance of HSCR trait varies from 5 to 70%. Trisomy 21 (T21) also predisposes to HSCR. We were able to collect a series of 393 patients affected by CCHS (n = 173), WS4 (n = 24), BBS (n = 51), MWS (n = 71), T21 (n = 46), and mental retardation (MR) with HSCR (n = 28). For each syndrome, we studied the RET locus in two subgroups of patients; i.e., with or without HSCR. We genotyped the RET locus in 393 patients among whom 195 had HSCR, and compared the distribution of alleles and genotypes within the two groups for each syndrome. RET acts as a modifier gene for the HSCR phenotype in patients with CCHS, BBS, and Down syndrome, but not in patients with MWS and WS4. The frequent, low penetrant, predisposing allele of the RET gene can be regarded as a risk factor for the HSCR phenotype in CCHS, BBS, and Down syndrome, while its role is not significant in MWS and WS4. These data highlight the pivotal role of the RET gene in both isolated and syndromic HSCR.
Asunto(s)
Alelos , Epistasis Genética , Enfermedad de Hirschsprung/genética , Proteínas Proto-Oncogénicas c-ret/genética , Femenino , Frecuencia de los Genes , Genotipo , Humanos , Masculino , Penetrancia , SíndromeRESUMEN
Hirschsprung's disease (HSCR) is a common congenital malformation characterized by the absence of intramural ganglion cells of the hindgut. Recently, mutations of the RET tyrosine kinase receptor have been identified in 50 and 15-20% of familial and sporadic HSCR, respectively. These mutations include deletion, insertion, frameshift, nonsense, and missense mutations dispersed throughout the RET coding sequence. To investigate their effects on RET function, seven HSCR missense mutations were introduced into either a 1114-amino acid wild-type RET isoform (RET51) or a constitutively activated form of RET51 (RET-MEN 2A). Here, we report that one mutation affecting the extracytoplasmic cadherin domain (R231H) and two mutations located in the tyrosine kinase domain (K907E, E921K) impaired the biological activity of RET-MEN 2A when tested in Rat1 fibroblasts and pheochromocytoma PC12 cells. However, the mechanisms resulting in RET inactivation differed since the receptor bearing R231H extracellular mutation resulted in an absent RET protein at the cell surface while the E921K mutation located within the catalytic domain abolished its enzymatic activity. In contrast, three mutations mapping into the intracytoplasmic domain neither modified the transforming capacity of RET-MEN 2A nor stimulated the catalytic activity of RET in our ligand-independent system (S767R, P1039L, M1064T). Finally, the C609W HSCR mutation exerts a dual effect on RET since it leads to a decrease of the receptor at the cell surface and converted RET51 into a constitutively activated kinase due to the formation of disulfide-linked homodimers. Taken together, our data show that allelic heterogeneity at the RET locus in HSCR is associated with various molecular mechanisms responsible for RET dysfunction.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales , Proteínas Adaptadoras del Transporte Vesicular , Proteínas de Drosophila , Enfermedad de Hirschsprung/genética , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/fisiología , Proteínas Tirosina Quinasas Receptoras/genética , Proteínas Tirosina Quinasas Receptoras/fisiología , Células 3T3 , Alelos , Animales , Biotinilación , Cadherinas/genética , Fibroblastos , Expresión Génica , Enfermedad de Hirschsprung/metabolismo , Humanos , Técnicas para Inmunoenzimas , Proteínas de la Membrana/metabolismo , Ratones , Mutagénesis Sitio-Dirigida , Fosforilación , Proteínas Tirosina Quinasas/genética , Proteínas/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas c-ret , Proteínas Tirosina Quinasas Receptoras/metabolismo , Proteínas Adaptadoras de la Señalización Shc , Transducción de Señal/genética , Proteína Transformadora 1 que Contiene Dominios de Homología 2 de Src , Transformación Genética , Células Tumorales CultivadasRESUMEN
BACKGROUND: In Hirschsprung's disease (HSCR), a hypomorphic allele of a major gene, RET, accounts for most isolated (non-syndromic) cases, along with other autosomal susceptibility loci under a multiplicative model. However, some syndromic forms of HSCR are monogenic entities, for which the disease causing gene is known. OBJECTIVE: To determine whether RET could be considered a modifier gene for the enteric phenotype on the background of a monogenic trait. METHODS: The syndromic HSCR entities studied were congenital central hypoventilation (CCHS) and Mowat-Wilson syndrome (MWS), caused by PHOX2B and ZFHX1B gene mutations, respectively. The RET locus was genotyped in 143 CCHS patients, among whom 44 had HSCR, and in 30 MWS patients, among whom 20 had HSCR. The distribution of alleles, genotypes, and haplotypes was compared within the different groups. To test the interaction in vivo, heterozygous mice were bred for a null allele of Phox2b and Ret genes. RESULTS: RET was shown to act as a modifier gene for the HSCR phenotype in patients with CCHS but not with MWS. The intestine of double heterozygote mice was indistinguishable from their littermates. A loss of over 50% of each gene function seemed necessary in the mouse model for an enteric phenotype to occur. CONCLUSIONS: In CCHS patients, the weak predisposing haplotype of the RET gene can be regarded as a quantitative trait, being a risk factor for the HSCR phenotype, while in MWS, for which the HSCR penetrance is high, the role of the RET predisposing haplotype is not significant. It seems likely that there are both RET dependent and RET independent HSCR cases.
Asunto(s)
Alelos , Enfermedad de Hirschsprung/genética , Mutación , Proteínas Proto-Oncogénicas c-ret/genética , Animales , Mapeo Cromosómico , Análisis Mutacional de ADN , Femenino , Frecuencia de los Genes , Haplotipos , Enfermedad de Hirschsprung/diagnóstico , Proteínas de Homeodominio/genética , Humanos , Masculino , Ratones , Linaje , Fenotipo , Polimorfismo de Nucleótido Simple , Síndrome , Factores de Transcripción/genéticaRESUMEN
BACKGROUND: The acronym CHARGE refers to a non-random cluster of malformations including coloboma, heart malformation, choanal atresia, retardation of growth and/or development, genital anomalies, and ear anomalies. This set of multiple congenital anomalies is frequent, despite rare patients with normal intelligence, and prognosis remains poor. Recently, CHD7 gene mutations have been identified in CHARGE patients; however, the function of CHD7 during development remains unknown. METHODS: We studied a series of 10 antenatal cases in whom the diagnosis of CHARGE syndrome was suspected, considering that a careful pathological description would shed light on the CHD7 function during development. CHD7 sequence analysis and in situ hybridisation were employed. RESULTS: The diagnosis of CHARGE syndrome was confirmed in all 10 fetuses by the identification of a CHD7 heterozygous truncating mutation. Interestingly, arhinencephaly and semi-circular canal agenesis were two constant features which are not included in formal diagnostic criteria so far. In situ hybridisation analysis of the CHD7 gene during early human development emphasised the role of CHD7 in the development of the central nervous system, internal ear, and neural crest of pharyngeal arches, and more generally showed a good correlation between specific CHD7 expression pattern and the developmental anomalies observed in CHARGE syndrome. CONCLUSIONS: These results allowed us to further refine the phenotypic spectrum of developmental anomalies resulting from CHD7 dysfunction.
Asunto(s)
Anomalías Múltiples/genética , ADN Helicasas/genética , Proteínas de Unión al ADN/genética , Desarrollo Embrionario/genética , Enfermedades Fetales/genética , Mutación , Eliminación de Secuencia , Secuencia de Bases , ADN/genética , ADN/aislamiento & purificación , Cartilla de ADN , Femenino , Humanos , Hibridación in Situ , Fenotipo , Embarazo , Diagnóstico Prenatal , Regiones Promotoras Genéticas , SíndromeRESUMEN
BACKGROUND: Majeed syndrome is an autosomal recessive, autoinflammatory disorder characterised by chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anaemia. The objectives of this study were to map, identify, and characterise the Majeed syndrome causal gene and to speculate on its function and role in skin and bone inflammation. METHODS: Six individuals with Majeed syndrome from two unrelated families were identified for this study. Homozygosity mapping and parametric linkage analysis were employed for the localisation of the gene responsible for Majeed syndrome. Direct sequencing was utilised for the identification of mutations within the genes contained in the region of linkage. Expression studies and in silico characterisation of the identified causal gene and its protein were carried out. RESULTS: The phenotype of Majeed syndrome includes inflammation of the bone and skin, recurrent fevers, and dyserythropoietic anaemia. The clinical picture of the six affected individuals is briefly reviewed. The gene was mapped to a 5.5 cM interval (1.8 Mb) on chromosome 18p. Examination of genes in this interval led to the identification of homozygous mutations in LPIN2 in affected individuals from the two families. LPIN2 was found to be expressed in almost all tissues. The function of LPIN2 and its role in inflammation remains unknown. CONCLUSIONS: We conclude that homozygous mutations in LPIN2 result in Majeed syndrome. Understanding the aberrant immune response in this condition will shed light on the aetiology of other inflammatory disorders of multifactorial aetiology including isolated chronic recurrent multifocal osteomyelitis, Sweet syndrome, and psoriasis.
Asunto(s)
Anemia Diseritropoyética Congénita/genética , Homocigoto , Mutación , Proteínas Nucleares/genética , Osteomielitis/genética , Adulto , Animales , Causalidad , Enfermedad Crónica , Secuencia Conservada , Análisis Mutacional de ADN , Familia , Femenino , Ligamiento Genético , Humanos , Jordania , Masculino , Especificidad de Órganos/genética , Linaje , Fenotipo , Recurrencia , Síndrome de Sweet/genética , SíndromeRESUMEN
Allgrove syndrome (triple A syndrome) is a rare autosomal recessive disorder characterized by achalasia, alacrima, adrenal insufficiency, and--occasionally--autonomic instability. Disease causing mutations have been found in the AAAS gene on 12q13, but no strong phenotype-genotype correlation could be found. We present a 28 year-old woman with classical systemic features of triple A syndrome with prominent neurological dysfunctions/deficits, including distal muscular atrophy, progressive muscle weakness and wasting of both legs, sensibility dysfunction, hyperreflexia and autonomic dysfunction presented with excessive sweating. DNA sequencing of the AAAS gene revealed compound heterozygosity for previously reported mutations. A similar genotype was previously reported, but with a remarkably different phenotype.
Asunto(s)
Enfermedades del Sistema Nervioso Autónomo/genética , Acalasia del Esófago/genética , Heterogeneidad Genética , Enfermedades del Aparato Lagrimal/genética , Proteínas de Complejo Poro Nuclear/genética , Adulto , Atrofia/complicaciones , Atrofia/patología , Enfermedades del Sistema Nervioso Autónomo/complicaciones , Análisis Mutacional de ADN/métodos , Dilatación/instrumentación , Acalasia del Esófago/complicaciones , Acalasia del Esófago/terapia , Femenino , Gastritis/complicaciones , Gastritis/genética , Humanos , Enfermedades del Aparato Lagrimal/complicaciones , Músculo Esquelético/patología , Proteínas del Tejido Nervioso , Mutación Puntual/genética , SíndromeAsunto(s)
Proteína de Unión a CREB/genética , Enfermedad de Hirschsprung/complicaciones , Enfermedad de Hirschsprung/genética , Síndrome de Rubinstein-Taybi/complicaciones , Síndrome de Rubinstein-Taybi/genética , Eliminación de Secuencia/genética , Femenino , Humanos , Recién Nacido , Masculino , EmbarazoRESUMEN
BACKGROUND: Evidence indicates that patients with familial achalasia associated with Allgrove or triple-A syndrome (i.e. alacrima, achalasia and adrenocorticotropin-resistant adrenal insufficiency with neurological impairment) have mutations of the alacrima achalasia adrenal insufficiency syndrome (AAAS) gene. AIM: The present study was aimed at identifying possible AAAS gene mutations in patients with established idiopathic non-familial achalasia. METHODS: Genomic DNA of 41 patients was isolated from peripheral blood cells using standard methods. The 16 exons of the AAAS gene (or ALADIN) were screened for mutations using the denaturing high-performance liquid chromatography method. RESULTS: Four heterozygous nucleotidic variations have been identified in patients with idiopathic achalasia, among which three were exonic conservative polymorphisms [i.e. D138D (GAT-->GAC), L227L (TTG-->CTG) and F285F (TTC-->TTT) in exons 5, 7 and 9, respectively]. The fourth nucleotidic variation was located in intron 13 (IVS14-23delT). All variants have been regarded as polymorphisms resulting in a normal ALADIN protein since they are either conservative or lying outside the consensus splice sites. CONCLUSIONS: Our data do not support a pathogenetic role for common AAAS gene mutations in patients with idiopathic achalasia as seen in Allgrove syndrome. These findings suggest the participation of different mechanisms in the pathogenesis of idiopathic achalasia.
Asunto(s)
Acalasia del Esófago/genética , Proteínas/genética , Adulto , Anciano , Acalasia del Esófago/fisiopatología , Femenino , Variación Genética , Humanos , Masculino , Persona de Mediana Edad , Mutación , Proteínas del Tejido Nervioso , Proteínas de Complejo Poro Nuclear , Polimorfismo GenéticoRESUMEN
Familial glucocorticoid deficiency due to corticotropin (ACTH) resistance consists of two distinct genetic syndromes that are both inherited as autosomal recessive traits: isolated ACTH resistance (iACTHR), which may be caused by inactivating mutations of the ACTH receptor (the MC2R gene) or mutations in an as yet unknown gene(s), and Allgrove syndrome (AS). The latter is also known as triple-A syndrome (MIM 231550). In three large cohorts of AS kindreds, the disease has been mapped to chromosome 12; most recently, mutations in the AAAS gene on 12q13 were found in these AS families. AAAS codes for the WD-repeat containing ALADIN (for alacrima-achalasia-adrenal insufficiency-neurologic disorder) protein. We investigated families with iACTHR (n = 4) and AS (n = 6) and a Bedouin family with ACTHR and a known defect of the TSH receptor. Four AS families were of mixed extraction from Puerto Rico (PR); most of the remaining six families were Caucasian families from North America (NA). Sequencing analysis found no MC2R genetic defects in any of the kindreds. No iACTHR kindreds, but all of AS families, had AAAS mutations. The previously reported IVS14+1G-->A splice donor mutation was found in all PR families, apparently due to a founder effect; one NA kindred was heterozygous for this mutation. In the latter family, long-range PCR failed to identify a deletion or other rearrangements of the AAAS gene. No other heterozygote or transmitting parent had any phenotype that could be considered part of AS. The IVS14+1G-->A mutation results in a premature termination of the predicted protein; although it was present in all PR families (in the homozygote state in three of them), there was substantial clinical variation between them. One PR family also carried a novel splice donor mutation of the AAAS gene in exon 11, IVS11+1G-->A; the proband was a compound heterozygote. A novel point mutation, 43C-->A(Gln15Lys), in exon 1 of the AAAS gene was identified in the homozygote state in a Canadian AS kindred with a milder AS phenotype. The predicted amino acid substitution in this family is located in a sequence that may participate in the preservation of stability of ALADIN beta-strands, whereas the splicing mutation in exon 11 may interfere with the formation of WD repeats in this molecule. We conclude that 1) AAAS does not appear to be frequently mutated in families with iACTHR; 2) AAAS is mutated in AS families from PR (that had previously been mapped to 12q13) and NA; and, 3) there is significant clinical variability between patients with the same AAAS defect.
Asunto(s)
Hormona Adrenocorticotrópica/sangre , Hormona Adrenocorticotrópica/fisiología , Glucocorticoides/deficiencia , Mutación/genética , Proteínas/genética , ADN/genética , ADN/aislamiento & purificación , Exones/genética , Genotipo , Humanos , Intrones/genética , Proteínas del Tejido Nervioso , Proteínas de Complejo Poro Nuclear , Fenotipo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Síndrome , Tirotropina/fisiologíaRESUMEN
Triple A syndrome (Allgrove syndrome, MIM No. 231550) is a rare autosomal recessive disorder characterised by ACTH-resistant adrenal insufficiency, achalasia of the cardia, and alacrimia. The triple A gene has been previously mapped to chromosome 12q13 in a maximum interval of 6 cM between loci D12S1629 and D12S312. Using linkage analysis in 12 triple A families, mostly originating from North Africa, we confirm that the disease locus maps to the 12q13 region (Zmax = 10.89 at theta = 0 for D12S1604) and suggest that triple A is a genetically homogeneous disorder. Recombination events as well as homozygosity for polymorphic markers enabled us to reduce the genetic interval to a 3.9 cM region. Moreover, total linkage disequilibrium was found at the D12S1604 locus between a rare allele and the mutant chromosomes in North African patients. Analysis of markers at five contiguous loci showed that most of the triple A chromosomes are derived from a single founder chromosome. As all markers are located in a 0 cM genetic interval and only allele 5 at the D12S1604 locus was conserved in mutant chromosomes, we speculate that the triple A mutation is due to an ancient Arabian founder effect that occurred before migration to North Africa. Since we also found linkage disequilibrium at D12S1604 in two patients from Southern Europe (France and Spain), the founder effect might well extend to other Mediterranean countries. Taking advantage of a YAC contig encompassing the triple A minimal physical region, the triple A gene was mapped to a 1.7 Mb DNA fragment accessible to gene cloning.