RESUMEN

BACKGROUND: FG syndrome (FGS) is an X-linked disorder characterised by mental retardation, hypotonia, particular dysmorphic facial features, broad thumbs and halluces, anal anomalies, constipation, and abnormalities of the corpus callosum. A behavioural phenotype of hyperactivity, affability, and excessive talkativeness is very frequent. The spectrum of clinical findings attributed to FGS has widened considerably since the initial description of the syndrome by Opitz and Kaveggia in 1974 and has resulted in clinical variability and genetic heterogeneity. In 2007, a recurrent R961W mutation in the MED12 gene at Xq13 was found to cause FGS in six families, including the original family described by Opitz and Kaveggia. The phenotype was highly consistent in all the R961W positive patients. METHODS: In order to determine the prevalence of MED12 mutations in patients clinically diagnosed with FGS and to clarify the phenotypic spectrum of FGS, 30 individuals diagnosed previously with FGS were evaluated clinically and by MED12 sequencing. RESULTS: The R961W mutation was identified in the only patient who had the typical phenotype previously associated with this mutation. The remaining 29 patients displayed a wide variety of features and were shown to be negative for mutations in the entire MED12 gene. A definite or possible alternative diagnosis was identified in 10 of these patients. CONCLUSION: This report illustrates the difficulty in making a clinical diagnosis of FGS given the broad spectrum of signs and symptoms that have been attributed to the syndrome. Individuals with a phenotype consistent with FGS require a thorough genetic evaluation including MED12 mutation analysis. Further genetic testing should be considered in those who test negative for a MED12 mutation to search for an alternative diagnosis.

Asunto(s)

Anomalías Múltiples/diagnóstico , Anomalías Múltiples/genética , Discapacidad Intelectual Ligada al Cromosoma X/diagnóstico , Discapacidad Intelectual Ligada al Cromosoma X/genética , Anomalías Múltiples/patología , Adolescente , Sustitución de Aminoácidos , Niño , Preescolar , Femenino , Humanos , Masculino , Complejo Mediador , Discapacidad Intelectual Ligada al Cromosoma X/patología , Hipotonía Muscular/diagnóstico , Hipotonía Muscular/genética , Hipotonía Muscular/patología , Mutación , Fenotipo , Receptores de Hormona Tiroidea/genética , Síndrome

Asunto(s)

Trastorno Autístico/genética , Discapacidad Intelectual/genética , Proteína Accesoria del Receptor de Interleucina-1/genética , Niño , Inversión Cromosómica , Cromosomas Humanos X , Humanos , Masculino

RESUMEN

We have studied a male patient with significant developmental delay, growth failure, hypotonia, girdle weakness, microcephaly, and multiple congenital anomalies including atrial (ASD) and ventricular (VSD) septal defects. Detailed cytogenetic and molecular analyses revealed three de novo X chromosome aberrations and a karyotype 46,Y,der(X)inv(X) (p11.4q11.2)inv(X)(q11.2q21.32 approximately q22.2)del(X)(q22.3q22.3) was determined. The three X chromosome aberrations in the patient include: a pericentric inversion (inv 1) that disrupted the Duchenne muscular dystrophy (DMD) gene, dystrophin, at Xp11.4; an Xq11.2q21.32 approximately q22.2 paracentric inversion (inv 2) putatively affecting no genes; and an interstitial deletion at Xq22.3 that results in functional nullisomy of several known genes, including a gene previously associated with X-linked nonsyndromic mental retardation, acyl-CoA synthetase long chain family member 4 (ACSL4). These findings suggest that the disruption of DMD and the absence of ACSL4 in the patient are responsible for neuromuscular disease and cognitive impairment.

Asunto(s)

Anomalías Múltiples/genética , Coenzima A Ligasas/genética , Discapacidades del Desarrollo/genética , Distrofina/genética , Discapacidad Intelectual/genética , Hipotonía Muscular/genética , Peso al Nacer , Niño , Aberraciones Cromosómicas , Cromosomas Humanos X , Femenino , Humanos , Recién Nacido , Masculino , Eliminación de Secuencia

RESUMEN

A patient with microcephaly, microphthalmia, ectrodactyly, and prognathism (MMEP) and mental retardation was previously reported to carry a de novo reciprocal t(6;13)(q21;q12) translocation. In an attempt to identify the presumed causative gene, we mapped the translocation breakpoints using fluorescence in situ hybridisation (FISH). Two overlapping genomic clones crossed the breakpoint on the der(6) chromosome, locating the breakpoint region between D6S1594 and D6S1250. Southern blot analysis allowed us to determine that the sorting nexin 3 gene (SNX3) was disrupted. Using Inverse PCR, we were able to amplify and sequence the der(6) breakpoint region, which exhibited homology to a BAC clone that contained marker D13S250. This clone allowed us to amplify and sequence the der(13) breakpoint region and to determine that no additional rearrangement was present at either breakpoint, nor was another gene disrupted on chromosome 13. Therefore, the translocation was balanced and SNX3 is probably the candidate gene for MMEP in the patient. However, mutation screening by dHPLC and Southern blot analysis of another sporadic case with MMEP failed to detect any point mutations or deletions in the SNX3 coding sequence. Considering the possibility of positional effect, another candidate gene in the vicinity of the der(6) chromosome breakpoint may be responsible for MMEP in the original patient or, just as likely, the MMEP phenotype in the two patients results from genetic heterogeneity.

Asunto(s)

Anomalías Múltiples/genética , Proteínas Portadoras/genética , Cromosomas Humanos Par 13/genética , Cromosomas Humanos Par 6/genética , Microcefalia/genética , Prognatismo/genética , Translocación Genética/genética , Proteínas de Transporte Vesicular/genética , Empalme Alternativo/genética , Secuencia de Aminoácidos , Secuencia de Bases , Proteínas Portadoras/química , Rotura Cromosómica/genética , Clonación Molecular , Análisis Mutacional de ADN , Femenino , Deformidades Congénitas del Pie/genética , Heterogeneidad Genética , Humanos , Hibridación Fluorescente in Situ , Discapacidad Intelectual/genética , Masculino , Datos de Secuencia Molecular , Fenotipo , Mapeo Físico de Cromosoma , Sitios de Empalme de ARN/genética , Nexinas de Clasificación , Proteínas de Transporte Vesicular/química

RESUMEN

Enamelin is the largest protein in the enamel matrix of developing teeth. In the pig, enamelin is secreted as 186-kDa phosphorylated glycoprotein, which is rapidly processed by enamel proteinases into smaller cleavage products. During the secretory stage of enamel formation, enamelin is found among the crystallites in the rod and interrod enamel and comprises roughly 5% of total matrix protein. Although the function of enamelin is unknown, it is thought to participate in enamel crystal nucleation and extension, and the regulation of crystal habit. Here we report the results of enamelin in situ hybridization in a day 1 mouse developing incisor that shows that enamelin is expressed by ameloblasts, but not by odontoblasts or other cells in the dental pulp. The restricted pattern of enamelin expression makes the human enamelin gene a prime candidate in the etiology of amelogenesis imperfecta (AI), a genetic disease in which defects of enamel formation occur in the absence of non-dental symptoms. We have cloned and characterized a full-length human enamelin cDNA and determined by radiation hybrid mapping and fluorescent in situ hybridization (FISH) that the gene is located on chromosome 4q near the ameloblastin gene in a region previously linked to local hypoplastic AI in six families. These findings will facilitate the search for specific mutations in the enamelin gene in kindreds suffering from amelogenesis imperfecta.

Asunto(s)

Cromosomas Humanos Par 4/genética , Clonación Molecular , ADN Complementario/genética , Proteínas del Esmalte Dental/genética , Odontogénesis/genética , Ameloblastos/metabolismo , Amelogénesis/genética , Amelogénesis Imperfecta/genética , Animales , Niño , Mapeo Cromosómico , Cristalización , Pulpa Dental/citología , Regulación de la Expresión Génica , Humanos , Hibridación in Situ , Hibridación Fluorescente in Situ , Incisivo , Ratones , Tercer Molar , Mutación/genética , Odontoblastos/metabolismo , Porcinos

Asunto(s)

Cromosomas Humanos Par 19 , Calicreínas , Serina Endopeptidasas/genética , Mapeo Cromosómico , Humanos , Hibridación Fluorescente in Situ

RESUMEN

Deletions of chromosome 18q are among the most common segmental aneusomies compatible with life. The estimated frequency is approximately 1/40,000 live births [Cody JD, Pierce JF, Brkanac Z, Plaetke R, Ghidoni PD, Kaye CI, Leach RJ. 1997. Am. J. Med. Genet. 69:280-286]. Most deletions are terminal encompassing as much as 36 Mb, but interstitial deletions have also been reported. We have evaluated 42 subjects with deletions of 18q at our institution. This is the largest number of individuals with this chromosome abnormality studied by one group of investigators. Here we report the physical findings in these individuals. We have compared our findings with those of previously reported cases and have found a significantly different incidence of several minor anomalies in our subjects. We also describe here several anomalies not previously reported in individuals with deletions of 18q, including short frenulum, short palpebral fissures, disproportionate short stature, overlap of second and third toes, and a prominent abdominal venous pattern. Characteristics found in subjects were analyzed for correlation with cytogenetic breakpoints. Several traits were found to correlate with the extent of the deletion. Large deletions were associated with significantly decreased head circumference and ear length as well as the presence of proximally placed and/or anomalous thumbs. Individuals with the smallest deletions were more likely to have metatarsus adductus. Although relatively few genotype/phenotype correlations were apparent, these data demonstrate that correlations with breakpoint are possible. This implies that more correlations will become evident when the more precise molecularly based genotyping is completed. These correlations will identify critical regions on the chromosome in which genes responsible for specific abnormal phenotypes are located.

Asunto(s)

Antropometría , Deleción Cromosómica , Cromosomas Humanos Par 18 , Anomalías Congénitas/genética , Adolescente , Adulto , Peso al Nacer , Niño , Preescolar , Mapeo Cromosómico , Anomalías Congénitas/clasificación , Femenino , Humanos , Lactante , Masculino , Sistema de Registros , Texas

RESUMEN

Yin Yang 1 (YY1) is a protein that activates and represses transcription of a large number of cellular and viral genes. In addition, studies suggest that YY1 may play an important role in development and differentiation. Here, we report the isolation and analysis of a YY1 genomic clone from a lambda human liver library. Fluorescence in situ hybridization with the YY1 clone has localized the YY1 gene to chromosome 14 band q32. A major YY1 gene transcription initiation site has been mapped to 478 bp upstream of the ATG translation start site. The proximal promoter contains multiple Sp1 transcription factor binding sites but lacks a consensus TATA or CCAAT box. Transient transfections and detailed deletion analyses localized the promoter to no more than 277 bp upstream from the major transcription start site. Finally, we have found that overexpression of the adenovirus E1A protein represses expression of a reporter gene directed by the YY1 promoter.

Asunto(s)

Proteínas de Unión al ADN/genética , Factores de Transcripción/genética , Proteínas E1A de Adenovirus/genética , Secuencia de Bases , Mapeo Cromosómico , Cromosomas Humanos Par 14/genética , Clonación Molecular , ADN/genética , Cartilla de ADN/genética , Factores de Unión al ADN Específico de las Células Eritroides , Expresión Génica , Genes Reporteros , Humanos , Hibridación Fluorescente in Situ , Datos de Secuencia Molecular , Reacción en Cadena de la Polimerasa , Regiones Promotoras Genéticas , Transfección , Factor de Transcripción YY1

RESUMEN

The majority of patients with 18q- syndrome appear cytogenetically to have a terminal deletion of the long arm of chromosome 18. These 18q- patients are diagnosed by use of standard cytogenetic banding techniques, which have resolution insufficient for precise genotyping. In our effort to obtain a thorough genotype, we have analyzed the DNA from 35 patients who originally were diagnosed as having de novo terminal deletions of chromosome 18. Molecular analysis was performed with polymorphic markers throughout the 18q- region. Cytogenetic FISH was performed with two human 18q telomeric probes, a chromosome 18-specific alpha-satellite probe, and whole chromosome 18-specific paint. Of 35 patients previously reported to have terminal deletions of 18q, we found that 5 (14%) have more-complex cryptic rearrangements and that 3 (9%) retain the most distal portion of 18q, consistent with an interstitial rather than a terminal deletion. These findings indicate that a standard karyotype can lead to insufficient characterization in 18q- syndrome. This has important ramifications for phenotype mapping of this syndrome, as well as for proper prognosis.

Asunto(s)

Deleción Cromosómica , Cromosomas Humanos Par 18 , Reordenamiento Génico , Bandeo Cromosómico , Humanos , Hibridación Fluorescente in Situ , Cariotipificación , Síndrome

RESUMEN

We report on a mother and child with a paracentric inversion of the long arm of chromosome 18: 46,XX,inv(18)(q21.1q23). The child had findings in common with those seen in 18q- syndrome including: microcephaly, epicanthal folds, midface hypoplasia, and abnormally modeled ears, dermatoglyphic whorls on fingertips, clubfeet, hearing loss, and developmental delay. The mother and several maternal relatives had mild mental retardation and hearing loss. Magnetic resonance imaging of the child's brain showed abnormal myelination. Molecular studies including PCR-based markers for the MBP locus and fluorescent in situ hybridization with a P1 genomic clone on mother and child demonstrated only one copy of the MBP locus (18q23) with the deletion extending beyond the MBP locus. Therefore, the deletion in the MBP region may account for the abnormal myelination seen in the patient. The other clinical findings, including mental retardation and hearing loss in this family, may reflect disruption of distal or proximal genes within the deleted MBP region or at the more proximal breakpoint 18q21.1, and may represent a contiguous gene syndrome. Further study of this family may help define those genes functioning in the MBP region that contribute to the phenotype of 18q- syndrome.

Asunto(s)

Centrómero/genética , Inversión Cromosómica , Cromosomas Humanos Par 18/genética , Pérdida Auditiva Bilateral/genética , Discapacidad Intelectual/genética , Adulto , Femenino , Genotipo , Pérdida Auditiva Bilateral/diagnóstico , Humanos , Hibridación Fluorescente in Situ , Lactante , Discapacidad Intelectual/diagnóstico , Leucocitos

RESUMEN

Idiopathic generalized epilepsies account for about 40% of epilepsy up to age 40 and commonly have a genetic basis. One type is benign familial neonatal convulsions (BFNC), a dominantly inherited disorder of newborns. We have identified a sub-microscopic deletion of chromosome 20q13.3 that co-segregates with seizures in a BFNC family. Characterization of cDNAs spanning the deleted region identified one encoding a novel voltage-gated potassium channel, KCNQ2, which belongs to a new KQT-like class of potassium channels. Five other BFNC probands were shown to have KCNQ2 mutations, including two transmembrane missense mutations, two frameshifts and one splice-site mutation. This finding in BFNC provides additional evidence that defects in potassium channels are involved in the mammalian epilepsy phenotype.

Asunto(s)

Epilepsia/genética , Mutación , Canales de Potasio/genética , Secuencia de Aminoácidos , Secuencia de Bases , Línea Celular Transformada , Deleción Cromosómica , Cromosomas Humanos Par 20 , ADN Complementario , Femenino , Humanos , Recién Nacido , Canal de Potasio KCNQ2 , Masculino , Datos de Secuencia Molecular , Linaje , Canales de Potasio con Entrada de Voltaje , Homología de Secuencia de Aminoácido

RESUMEN

Magnetic resonance imaging (MRI) and MRI relaxometry were used to investigate disturbed brain myelination in 18q- syndrome, a disorder characterized by mental retardation, dysmorphic features, and growth failure. T1-weighted and dual spin-echo T2-weighted MR images were obtained, and T1 and T2 parametric image maps were created for 20 patients and 12 controls. MRI demonstrated abnormal brain white matter in all patients. White matter T1 and T2 relaxation times were significantly prolonged in patients compared to controls at all ages studied, suggesting incomplete myelination. Chromosome analysis using fluorescence in situ hybridization techniques showed that all patients with abnormal MRI scans and prolonged white matter T1 and T2 relaxation times were missing one copy of the myelin basic protein (MBP) gene. The one patient with normal-appearing white matter and normal white matter T1 and T2 relaxation times possessed two copies of the MBP gene. MRI and molecular genetic data suggest that incomplete cerebral myelination in 18q- is associated with haploinsufficiency of the gene for MBP.

Asunto(s)

Anomalías Múltiples/genética , Encefalopatías Metabólicas/genética , Encéfalo/patología , Aberraciones Cromosómicas/genética , Deleción Cromosómica , Cromosomas Humanos Par 18/genética , Eliminación de Gen , Imagen por Resonancia Magnética , Proteína Básica de Mielina/genética , Vaina de Mielina/fisiología , Anomalías Múltiples/patología , Adolescente , Encefalopatías Metabólicas/patología , Niño , Preescolar , Aberraciones Cromosómicas/patología , Trastornos de los Cromosomas , Cromosomas Humanos Par 18/ultraestructura , Femenino , Humanos , Hibridación Fluorescente in Situ , Lactante , Masculino , Proteína Básica de Mielina/deficiencia , Vaina de Mielina/ultraestructura , Reacción en Cadena de la Polimerasa , Síndrome

RESUMEN

Amelogenesis imperfecta (AI) is a broad group of hereditary enamel defects that is characterized by a high degree of clinical diversity. Recently, the local hypoplastic form of autosomal dominant AI (AIH2) has been mapped to human chromosome 4q in a 17.6-cM region. This locus has been further refined to a 4-Mb interval between D4S2421 and Albumin. Recently, a cDNA clone for an enamel matrix protein, ameloblastin (AMBN), has been isolated. In this report, we have isolated a PAC human genomic clone containing the human AMBN gene. The AMBN was mapped by two color fluorescence in situ hybridization using two P1 genomic clones for sequence tagged site (STS) markers, D4S400 and D4S409, which flank the critical AIH2 region. Our results place AMBN at 4q21 between D4S409 (4q13) and D4S400 (4q21). Furthermore, the AMBN PAC genomic clone was shown to contain three STS markers, D4S2604, D4S2670, and D4S2609, which are contained within the critical region defined by six Swedish families with AIH2. AMBN is therefore a strong candidate gene for AIH2.

Asunto(s)

Amelogénesis Imperfecta/genética , Cromosomas Humanos Par 4/genética , Proteínas del Esmalte Dental/genética , Mapeo Cromosómico , Clonación Molecular , Genes Dominantes , Marcadores Genéticos , Humanos , Hibridación Fluorescente in Situ , Lugares Marcados de Secuencia

RESUMEN

We recently cloned a gene whose protein product binds to the Epstein-Barr virus BZLF1 gene promoter. The same gene has been previously cloned by another group who named it S mu bp-2 because its protein product binds to the S mu motif of the immunoglobulin heavy chain gene where it is postulated to function in immunoglobulin class switching. In the current study, we confirm that the S mu bp-2 gene is located on chromosome 11q13, a locus known to be altered by translocation in 50-70% of mantle cell lymphomas. We used Southern blot analysis to determine whether the S mu bp-2 gene was structurally rearranged in any of 25 mantle cell lymphomas. We found no evidence of rearrangement in any of these lymphomas including 18 that were proven to contain t(11;14) by cytogenetic analysis. These data suggest that structural alteration of the S mu bp-2 gene is not an underlying mechanism of tumorigenesis in mantle cell lymphomas.

Asunto(s)

Cromosomas Humanos Par 11 , Proteínas de Unión al ADN/genética , Linfoma no Hodgkin/genética , Factores de Transcripción , Translocación Genética , Proteínas Virales , Mapeo Cromosómico , Clonación Molecular , Células HeLa , Humanos , Datos de Secuencia Molecular , Regiones Promotoras Genéticas , Transactivadores/genética

Asunto(s)

Cromosomas Humanos Par 19 , Proteínas de Unión al ADN/genética , Proteínas de Unión a la Región de Fijación a la Matriz , Proteínas Asociadas a Matriz Nuclear , Proteínas Nucleares/genética , Receptores de Estrógenos , Mapeo Cromosómico , Humanos , Células Híbridas , Hibridación Fluorescente in Situ , Regiones Promotoras Genéticas , TATA Box

Asunto(s)

Mapeo Cromosómico , Cromosomas Humanos Par 4 , Sialoglicoproteínas/genética , Bandeo Cromosómico , Proteínas de la Matriz Extracelular , Humanos , Hibridación Fluorescente in Situ , Fosfoproteínas

Asunto(s)

Cromosomas Humanos Par 6 , Proteínas Nucleares/genética , Receptores de Superficie Celular/genética , Receptores Citoplasmáticos y Nucleares/genética , Factores de Transcripción/genética , Línea Celular , Mapeo Cromosómico , Humanos , Células Híbridas , Hibridación Fluorescente in Situ

RESUMEN

TR4 is a new member of the nuclear hormone receptor family. This receptor is highly conserved in rat and human, but an in-frame insertion of 19 amino acid residues in the amino-terminal (A/B) region was found in the human homolog, which we refer to as hTR4alpha1. By reverse transcription-PCR (RT-PCR) we have identified a human TR4 mRNA (hTR4alpha2) that is analogous in size and sequence to the reported rat TR4. RT-PCR analysis using total RNA derived from various rat tissues revealed a new rat TR4 transcript, referred to as rTR4alpha1, which is homologous to hTR4alpha1 since it contains the extra 19 amino acids in the A/B region. The two rat transcripts showed a differential tissue distribution. Analysis of the exon-intron organization of the hTR4 A/B region showed that the 19-amino-acid peptide insert in hTR4alpha1 was encoded by a separate exon, indicating that hTR4alpha1 and hTR4alpha2 transcripts were produced by the differential usage of the exon. RT-PCR analysis revealed that both hTR4alpha1 and hTR4alpha2 were detectable in brain, placenta, and ovary. In contrast, the human ovarian cancer cell line, PA1, failed to express hTR4alpha1. By fluorescence in situ hybridization, we have mapped the hTR4 gene to 3p25, a region deleted in some forms of cancer.

Asunto(s)

Mapeo Cromosómico , Cromosomas Humanos Par 3 , Variación Genética , Proteínas del Tejido Nervioso/biosíntesis , Proteínas del Tejido Nervioso/genética , Receptores Citoplasmáticos y Nucleares/genética , Receptores de Esteroides/biosíntesis , Receptores de Esteroides/genética , Receptores de Hormona Tiroidea , Animales , Secuencia de Bases , Encéfalo/metabolismo , Deleción Cromosómica , Cartilla de ADN , Exones , Femenino , Humanos , Hibridación Fluorescente in Situ , Intrones , Datos de Secuencia Molecular , Neoplasias/genética , Especificidad de Órganos , Ovario/metabolismo , Placenta/metabolismo , Reacción en Cadena de la Polimerasa , Embarazo , ARN Mensajero/biosíntesis , Ratas , Receptores Citoplasmáticos y Nucleares/biosíntesis , Transcripción Genética

RESUMEN

A glutamate binding subunit gene, GRINA, has been previously mapped to human chromosome 8. A form of inherited epilepsy, benign familial neonatal convulsions (BFNC), has also been localized to chromosome 8. As NMDA receptors have been implicated in the pathogenesis of epilepsy, we were interested in determining whether GRINA mapped to the same region of chromosome 8 as BFNC. Fluorescence in situ hybridization localized GRINA to band 8q24, distal to the thyroglobulin gene. The strongest signal was seen at 8q24.3. A panel of 97 radiation hybrids (RH) was used to verify the localization. The RH mapping results placed GRINA as the most telomeric marker on our map of 8q24, distal to the interval defined for BFNC.

Asunto(s)

Mapeo Cromosómico , Cromosomas Humanos Par 6/genética , Receptores de N-Metil-D-Aspartato/genética , Animales , Secuencia de Bases , Sitios de Unión/genética , Cartilla de ADN/genética , ADN Complementario/genética , Epilepsia/genética , Marcadores Genéticos , Ácido Glutámico/metabolismo , Humanos , Células Híbridas , Hibridación Fluorescente in Situ , Recién Nacido , Datos de Secuencia Molecular , Conformación Proteica , Ratas , Receptores de N-Metil-D-Aspartato/química , Receptores de N-Metil-D-Aspartato/metabolismo

RESUMEN

The collagenase type IV B gene (CLG4B) was previously mapped to human chromosome 16 by hybridization of a cDNA probe to DNAs from a somatic cell hybrid panel. We have relocalized CLG4B to chromosome 20 based on three different lines of evidence: screening a somatic cell hybrid mapping panel, fluorescence in situ hybridization (FISH), and linkage analysis using a newly identified polymorphism.

Asunto(s)

Cromosomas Humanos Par 20/genética , Colagenasas/genética , Secuencia de Bases , Ligamiento Genético , Humanos , Hibridación Fluorescente in Situ , Datos de Secuencia Molecular , Reacción en Cadena de la Polimerasa