Asunto(s)
Efecto Fundador , Proteínas/genética , Degeneración Retiniana/genética , Sustitución de Aminoácidos , Proteínas Portadoras , ADN/química , ADN/genética , Análisis Mutacional de ADN , Progresión de la Enfermedad , Proteínas del Ojo , Salud de la Familia , Femenino , Variación Genética , Heterocigoto , Histidina/genética , Homocigoto , Humanos , Masculino , Mutación , Países Bajos , Linaje , Degeneración Retiniana/patología , Tirosina/genética , cis-trans-IsomerasasRESUMEN
Möbius syndrome (MIM 157900) consists of a congenital paresis or paralysis of the VIIth (facial) cranial nerve, frequently accompanied by dysfunction of other cranial nerves. The abducens nerve is typically affected, and often, also, the hypoglossal nerve. In addition, orofacial and limb malformations, defects of the musculoskeletal system, and mental retardation are seen in patients with Möbius syndrome. Most cases are sporadic, but familial recurrence can occur. Different modes of inheritance are suggested by different pedigrees. Genetic heterogeneity of Möbius syndrome has been suggested by cytogenetic studies and linkage analysis. Previously, we identified a locus on chromosome 3q21-22, in a large Dutch family with Möbius syndrome consisting essentially of autosomal dominant asymmetric bilateral facial paresis. Here we report linkage analysis in a second large Dutch family with autosomal dominant inherited facial paresis. After exclusion of >90% of the genome, we identified the locus on the long arm of chromosome 10 in this family, demonstrating genetic heterogeneity of this condition. The reduced penetrance suggests that at least some of the sporadic cases might be familial.
Asunto(s)
Mapeo Cromosómico , Cromosomas Humanos Par 10/genética , Parálisis Facial/genética , Genes Dominantes/genética , Heterogeneidad Genética , Femenino , Marcadores Genéticos , Haplotipos , Heterocigoto , Humanos , Escala de Lod , Masculino , Países Bajos , Linaje , Penetrancia , Fenotipo , Polimorfismo Genético , Recombinación Genética/genéticaRESUMEN
A family is described in which X-linked mild to borderline mental retardation (MR) is associated with cleft lip/palate. Linkage analysis showed a maximum LOD score of Z=2.78 at straight theta=0.0 for the DXS441 locus with flanking markers DXS337 and DXS990, defining the region Xp11.3-q21.3 with a linkage interval of 25 cM.
Asunto(s)
Labio Leporino/complicaciones , Fisura del Paladar/complicaciones , Discapacidad Intelectual/genética , Cromosoma X/genética , Mapeo Cromosómico , ADN/genética , Salud de la Familia , Femenino , Ligamiento Genético , Humanos , Discapacidad Intelectual/complicaciones , Escala de Lod , Masculino , Repeticiones de Microsatélite , LinajeRESUMEN
Four families are described in which mental retardation segregates in an X-linked fashion. Mental retardation was the only consistent clinical finding in all affected males. The degree of retardation varied from mild to profound both between and within families. Linkage analysis localized the genetic defect of MRX43 to Xp22. 31-p21.2, MRX44 to Xp11.3-p11.21, MRX45 to Xp11.3-p11.21, and MRX52 to Xp11.21-q21.33 with LOD scores of >2 at straight theta = 0.0 in all four families.
Asunto(s)
Discapacidad Intelectual/genética , Cromosoma X/genética , Adulto , Anciano , Mapeo Cromosómico , ADN/genética , Salud de la Familia , Resultado Fatal , Femenino , Estudios de Seguimiento , Ligamiento Genético , Humanos , Discapacidad Intelectual/psicología , Escala de Lod , Masculino , Repeticiones de Microsatélite , Persona de Mediana Edad , Linaje , Escalas de Valoración Psiquiátrica , PsicometríaRESUMEN
We report linkage analysis in a new family with nonspecific X-linked mental retardation, using 27 polymorphic markers covering the entire X-chromosome. We could assign the underlying disease gene, denoted MRX65, to the pericentromeric region, with flanking markers DXS573 in Xp11.3 and DXS990 in Xq21.33. A maximum LOD score of 3.64 was found at markers ALAS2 (Xp11.22) and DXS453 (Xq12) at straight theta = 0. Twenty-five of the 58 reported MRX families are linked to a region that is partially overlapping with the region reported here. Extension of the pedigree showed a number of unaffected distant relatives with haplotypes corresponding to the disease locus. Apparently, a new mutation in a female is causative for the disease in the family reported here. Furthermore, we show the importance of combining clinical, cytogenetic, and molecular studies since one of the family members, expected to be affected by the same genetic defect, has a 48,XXXY karyotype.
Asunto(s)
Discapacidad Intelectual/genética , Cromosoma X/genética , Adulto , Pesos y Medidas Corporales , Centrómero/genética , Niño , ADN/genética , Salud de la Familia , Femenino , Ligamiento Genético , Humanos , Escala de Lod , Masculino , Repeticiones de Microsatélite , Persona de Mediana Edad , Mutación , Linaje , Escalas de Valoración Psiquiátrica , PsicometríaRESUMEN
We report on a family with an X linked neurodegenerative disorder consisting of mental retardation, blindness, convulsions, spasticity, and early death. Neuropathological examination showed mild hypomyelination. By linkage analysis, the underlying genetic defect could be assigned to the pericentromeric region of the X chromosome with a maximum lod score of 3.30 at theta=0.0 for the DXS1204 locus with DXS337 and PGK1P1 as flanking markers.
Asunto(s)
Ceguera/genética , Centrómero/genética , Discapacidad Intelectual/genética , Espasticidad Muscular/genética , Vaina de Mielina/genética , Enfermedades Neurodegenerativas/genética , Convulsiones/genética , Cromosoma X/genética , Mapeo Cromosómico , Diagnóstico Diferencial , Ligamiento Genético , Marcadores Genéticos , Humanos , Masculino , Linaje , SíndromeRESUMEN
Large deletions in Xq21 often are associated with contiguous gene syndromes consisting of X-linked deafness type 3 (DFN3), mental retardation (MRX), and choroideremia (CHM). The identification of deletions associated with classic CHM or DFN3 facilitated the positional cloning of the underlying genes, REP-1 and POU3F4, respectively, and enabled the positioning of the MRX gene in between these genes. Here, we report the cloning and characterization of a novel gene, ribosomal S6-kinase 4 (RSK4; HGMW-approved symbol RPS6KA6), which maps in the MRX critical region. RSK4 is completely deleted in eight patients with the contiguous gene syndrome including MRX, partially deleted in a patient with DFN3 and present in patients with an Xq21 deletion and normal intellectual abilities. RSK4 is most abundantly expressed in brain and kidney. The predicted protein of 746 amino acids shows a high level of homology to three previously isolated members of the human RSK family. RSK2 is involved in Coffin-Lowry syndrome and nonspecific MRX. The localization of RSK4 in the interval that is commonly deleted in mentally retarded males together with the high degree of amino acid identity with RSK2 suggests that RSK4 plays a role in normal neuronal development. Further mutation analyses in males with X-linked mental retardation must prove that RSK4 is indeed a novel MRX gene.
Asunto(s)
Coroideremia/genética , Discapacidad Intelectual/genética , Fosfotransferasas/genética , Proteínas Quinasas S6 Ribosómicas/genética , Proteínas Ribosómicas/metabolismo , Eliminación de Secuencia/genética , Secuencia de Aminoácidos , Secuencia de Bases , Northern Blotting , Mapeo Cromosómico , Clonación Molecular , Análisis Mutacional de ADN , Sordera/genética , Expresión Génica , Pruebas Genéticas , Humanos , Masculino , Datos de Secuencia Molecular , Reacción en Cadena de la Polimerasa , Proteína S6 Ribosómica , Análisis de Secuencia de ADN , Homología de Secuencia de Aminoácido , Cromosoma X/genéticaRESUMEN
We report linkage data on a new large family with non-specific X linked mental retardation (MRX), using 24 polymorphic markers covering the entire X chromosome. We could assign the underlying disease gene, denoted MRX46, to the Xq25-q26 region. MRX46 is tightly linked to the markers DXS8072, HPRT, and DXS294 with a maximum lod score of 5.12 at theta=0. Recombination events were observed with DXS425 in Xq25 and DXS984 at the Xq26-Xq27 boundary, which localises MRX46 to a 20.9 cM (12 Mb) interval. Several X linked mental retardation syndromes have been mapped to the same region of the X chromosome. In addition, the localisation of two MRX genes, MRX27 and MRX35, partially overlaps with the linkage interval obtained for MRX46. Although an extension of the linkage analysis for MRX35 showed only a minimal overlap with MRX46, it cannot be excluded that the same gene is involved in several of these MRX disorders. On the other hand, given the considerable genetic heterogeneity in MRX, one should be extremely cautious in using interfamilial linkage data to narrow down the localisation of MRX genes. Therefore, unless the underlying gene(s) is characterised by the analysis of candidate genes, MRX46 can be considered a new independent MRX locus.
Asunto(s)
Ligamiento Genético , Discapacidad Intelectual/genética , Cromosoma X , Adulto , Anciano , Mapeo Cromosómico , Marcadores Genéticos , Humanos , Escala de Lod , Hombres , Persona de Mediana Edad , LinajeRESUMEN
Linkage analysis is described in a family with X-linked mental retardation, ataxia, weakness, floppiness, delayed motor development, absence of deep tendon reflexes, hearing impairment and loss of vision (MIM no. 301835). The disease has a fatal course due to the susceptibility of the patients to infections, especially of the respiratory tract. Clinical signs indicate impairment of the posterior columns, peripheral motor and sensory neurons and the second and eighth cranial nerves and/or their nuclei. The involvement of the posterior columns of the spinal cord is further suggested by the almost complete absence of myelinated fibers therein. We localized the responsible gene(s) to Xq21.33-q24 between DXS1231 and DXS1001 with a maximum lod score of 6.97. The proteolipid protein gene, which codes for two myelin proteins of the central nervous system and is located in this region, was considered as a candidate gene for this disorder. However, no mutations were found in the protein-coding part of this gene.
Asunto(s)
Enfermedades Genéticas Congénitas/genética , Cromosoma X , Ataxia/genética , Ceguera/genética , Niño , Preescolar , Mapeo Cromosómico , Sordera/genética , Femenino , Enfermedades Genéticas Congénitas/mortalidad , Ligamiento Genético , Marcadores Genéticos , Humanos , Discapacidad Intelectual/genética , Masculino , Linaje , SíndromeRESUMEN
Möbius syndrome (MIM no. 157900) consists of a congenital paresis or paralysis of the VIIth cranial nerve, frequently accompanied by paralysis of other cranial nerves, orofacial and limb malformations, defects of the musculoskeletal system and mental retardation. Although most patients are sporadic cases, familial recurrence is not rare. Different pedigrees suggest different modes of inheritance. We performed linkage analysis in a large family with autosomal dominantly inherited Möbius syndrome, consisting essentially of asymmetric bilateral facial pareses. After exclusion of the candidate region for Möbius syndrome on 13q12.2-q13, we localized the gene to chromosome 3q21-22, indicating genetic heterogeneity of Möbius syndrome. This heterogeneity is further proven by the exclusion of both loci in a second family with Möbius syndrome.
Asunto(s)
Cromosomas Humanos Par 3/genética , Parálisis Facial/genética , Ligamiento Genético , Mapeo Cromosómico , Femenino , Humanos , Masculino , Países BajosRESUMEN
We report on several members of a family with varying degrees of X-linked mental retardation (XLMR), isolated growth hormone deficiency (IGHD), and infantile behaviour but without other consistent phenotypic abnormalities. Male patients continued to grow until well into their twenties and reached a height ranging from 135 to 159 cm. Except one, all female carriers were mentally normal; their adult height ranged from 159 to 168 cm. By linkage studies we have assigned the underlying genetic defect to the Xq24-q27.3 region, with a maximum lod score of Z = 3.26 at theta = 0.0 for the DXS294 locus. The XLMR-IGHD phenotype in these patients may be due to pleiotropic effects of a single gene or it may represent a contiguous gene syndrome.
Asunto(s)
Ligamiento Genético , Hormona de Crecimiento Humana/deficiencia , Discapacidad Intelectual/genética , Cromosoma X , Adulto , Anciano , Niño , Femenino , Tamización de Portadores Genéticos , Humanos , Masculino , Persona de Mediana Edad , LinajeRESUMEN
We report on a family in which nonsyndromal mild to moderate mental retardation segregates as an X-linked trait (MRX41). Two point linkage analysis demonstrated linkage between the disorder and marker DXS3 in Xq21.33 with a lod score of 2.56 at theta = 0.0 and marker DXS1108 in Xq28 with a lod score of 3.82 at theta = 0.0. Multipoint linkage analysis showed that the odds for a location of the gene in Xq28 vs Xq21.33 are 100:1. This is the fourth family with non-specific X-linked mental retardation with Xq28-qter as the most likely gene localization.
Asunto(s)
Mapeo Cromosómico , Ligamiento Genético , Discapacidad Intelectual/genética , Cromosoma X , Femenino , Humanos , Escala de Lod , Masculino , LinajeRESUMEN
Cowden disease (CD) (MIM 158350), or multiple hamartoma syndrome, is a rare autosomal dominant familial cancer syndrome with a high risk of breast cancer. Its clinical features include a wide array of abnormalities but the main characteristics are hamartomas of the skin, breast, thyroid, oral mucosa and intestinal epithelium. The pathognomonic hamartomatous features of CD include multiple smooth facial papules, acral keratosis and multiple oral papillomas. The pathological hallmark of the facial papules are multiple trichilemmomas. Expression of the disease is variable and penetrance of the dermatological lesions is assumed to be virtually complete by the age of twenty. Central nervous system manifestations of CD were emphasized only recently and include megalencephaly, epilepsy and dysplastic gangliocytomas of the cerebellum (Lhermitte-Duclos disease, LDD). Early diagnosis is important since female patients with CD are at risk of developing breast cancer. Other lesions include benign and malignant disease of the thyroid, intestinal polyps and genitourinary abnormalities. To localize the gene for CD, an autosomal genome scan was performed. A total of 12 families were examined, resulting in a maximum lod score of 8.92 at theta = 0.02 with the marker D10S573 located on chromosome 10q22-23.
Asunto(s)
Deleción Cromosómica , Cromosomas Humanos Par 10 , Síndrome de Hamartoma Múltiple/genética , Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/genética , Mapeo Cromosómico , Femenino , Ligamiento Genético , Marcadores Genéticos , Síndrome de Hamartoma Múltiple/diagnóstico , Humanos , Escala de Lod , Masculino , Linaje , Polimorfismo Genético , Factores de Riesgo , Programas InformáticosRESUMEN
In a family with autosomal dominant cystoid macular dystrophy (DCMD) linkage was detected with the dinucleotide marker D7S435 on the short arm of chromosome 7. With markers flanking D7S435, the DCMD locus could be assigned to the interval D7S493-D7S526 at 7p15-p21, which spans approximately 20 cM. Three-point linkage yielded a maximal lod score of 9.46 and location score of 43.5 and suggested that DCMD is 5,5 cM proximal to D7S493. Recently, a retinitis pigmentosa (RP7) locus has been mapped in roughly the same area of chromosome 7. Genetic data of both studies described below, allow a region of overlap between the location of the DCMD and the RP7 gene between D7S435 and D7S526. Both genes being one and the same will further substantiate the close relationship between macular degeneration and retinitis pigmentosa.