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Results for “Heterogeneity Mapping”

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PubMed2000

A second locus for an axonal form of autosomal recessive Charcot-Marie-Tooth disease maps to chromosome 19q13.3.

Autosomal recessive Charcot-Marie-Tooth disease (CMT) represents a heterogeneous group of disorders affecting the peripheral nervous system. The axonal form of the disease is designated as "CMT type 2" (CMT2), and one locus (1q21.2-q21.3) has been reported for the autosomal recessive form. Here we report the results of a genomewide search in an inbred Costa Rican family (CR-1) affected with autosomal recessive CMT2. By analyzing three branches of the family we detected linkage to the 19q13.3 region, and subsequent homozygosity mapping defined shared haplotypes between markers D19S902 and D19S907 in a 5.5-cM range. A maximum two-point LOD score of 9.08 was obtained for marker D19S867, at a recombination fraction of.00, which strongly supports linkage to this locus. The epithelial membrane protein 3 gene, encoding a PMP22 homologous protein and located on 19q13.3, was ruled out as being responsible for this form of CMT. The age at onset of chronic symmetric sensory-motor polyneuropathy was 28-42 years (mean 33.8 years); the electrophysiological data clearly reflect an axonal degenerative process. The phenotype and locus are different from those of demyelinating CMT4F, recently mapped to 19q13.1-13.3; hence, the disease affecting the Costa Rican family constitutes an axonal, autosomal recessive CMT subtype (ARCMT2B).

Adult↗

PubMed2006

A novel autosomal recessive limb-girdle muscular dystrophy with quadriceps atrophy maps to 11p13-p12.

Limb-girdle muscular dystrophies (LGMD) are a heterogeneous group of pathologies. We have identified a cohort of 14 French-Canadian patients from eight different families displaying a novel form of LGMD with an autosomal recessive inheritance. These patients share some features with previously described cases of 'quadriceps myopathy' that evolved into an LGMD. All demonstrate quadriceps femoris asymmetrical atrophy. Creatine kinase values were variable from normal to 6000 U/l. Clinical evaluations and MRI studies demonstrate a variable intrafamilial and interfamilial phenotype. Asymmetrical muscle involvement was clinically observed and confirmed by imaging. MRI studies suggest that the hamstrings and the adductor magnus are the first limb muscles to demonstrate fatty infiltration. Muscle pathology shows no sign of active inflammation but increased endomysial connective tissue associated with basal lamina duplication and collagen disorganization. A genome-wide scan using the two largest families uncovered linkage to marker D11S1360 on chromosome 11p12 [multipoint logarithm of the odds (LOD) score of 2.78]. Further genotyping for the eight families confirmed linkage to this new LGMD locus (multipoint LOD score of 4.56). Fine mapping subsequently defined a less than 3.3 cM candidate interval on 11p13-p12. Haplotype analysis of carrier chromosomes suggests that the most frequent mutation may account for up to 81.3% of French-Canadian mutations. In this study, we describe the chromosomal locus of a new form of recessive LGMD with prominent quadriceps femoris atrophy.

Adult↗

PubMed2002

A locus for simple pure febrile seizures maps to chromosome 6q22-q24.

Febrile seizures (FS) syndromes exhibit major clinical and genetic heterogeneity. We report a clinical and genetic study of three families with simple FS segregating as an autosomal dominant (AD) trait with high penetrance. All affected members presented a homogeneous phenotype of simple FS. The FS ceased before the age of 5 years. Among the 29 affected family members, only one patient presented two afebrile seizures, and none of the others developed concomitant or subsequent epilepsy. The phenotype differs from that previously reported in families presenting FS or generalized epilepsy with febrile seizures plus (GEFS+). After exclusion of already known loci for FS and GEFS+, we performed a genome-wide scan in the largest family. It led to the identification of a new locus on chromosome 6q22-q24 spanning 6.4 cM between D6S1620 and D6S975. For one of the other two families, the trait also segregated with this locus, but linkage studies could not restrict the candidate region further. The absence of linkage in the third family supports genetic heterogeneity of the AD form of pure simple FS. Sequence analysis excluded the implication of five candidate genes [A kinase anchoring protein 18 (AKAP18), syntaxin 7, putative neurotransmitter receptor (PNR), G protein receptor 57 (GPR57) and G protein receptor 58 (GPR58)] in the interval based on function. The locus mapping to 6q22-q24 seems to be the first identified locus responsible for pure simple FS, the most frequent form of FS. Studies are ongoing to identify the gene.

Adolescent↗

PubMed2006

Molecular genetics of autosomal-recessive axonal Charcot-Marie-Tooth neuropathies.

Autosomal-recessive forms of Charcot-Marie-Tooth (ARCMT) account for less than 10% of the families with CMT. On the other hand, in countries with a high prevalence of consanguinity this mode of inheritance accounts, likely, for the vast majority of CMT phenotypes. Like dominant forms, autosomal-recessive forms are generally subdivided into demyelinating forms (autosomal-recessive CMT1: ARCMT1 or CMT4) and axonal forms (ARCMT2). Until now, demyelinating ARCMT were more extensively studied at the genetic level than the axonal forms. Although the latter are undoubtedly the rarest forms among the heterogeneous group of CMT, three distinct forms have been genetically mapped and recent studies in the past 4 yr provided evidence that their respective causing genes have been characterized. Indeed, gene defects in encoding A-type lamins (LMNA), encoding Ganglioside-induced Differentiation-Associated Protein-1 (GDAP1) and encoding the mediator of RNA polymerase II transcription, subunit 25 homolog (MED25) have been identified in ARCMT2 subtypes. Given the clinical, electrophysiological and histological heterogeneity of CMT2, it is likely that unreported forms of ARCMT2, related to novel genes, remain to be discovered, leading to an even more complex classification. However, our goal in this review is to provide the reader with a clear view on the known genes and mechanisms involved in ARCMT2 and their associated phenotypes.

Animals↗

PubMed2006

Confocal microprobe Raman imaging of urban tropospheric aerosol particles.

Particulate matter with aerodynamic diameters of < 1, 1-2.5, and 2.5-10 microm were collected during two seasons in two urban zones situated northeast and southwest, respectively, of a lead/zinc smelter located in a former mining region of northern France. We demonstrate the effectiveness of the combined use of computer-controlled Raman mapping and multivariate curve resolution (MCR) of the Raman images to determine heterogeneous chemistry at the level of aerosol particle. The resulting molecular images of major species were found to be in accurate agreement with elemental images obtained by WDS X-ray-mapping. Environmental SEM was very useful to localize spare metal-rich particles before Raman mapping. Some spare particles containing pyromorphite (Pb5(PO4)3OH) and franklinite (ZnxFe3-xO4) mixed with mineral dust were detected at the northeast (NE) sampling site, when the wind was blowing from the west (W) sector. These particles were probably suspended in the troposphere by the action of wind or by mechanical disturbance of polluted top soils. The most abundantly encountered particles in the 10-2.5 and 2.5-1 microm fractions were found to be aggregates of NaCl, CaCO3, CaSO4 x 2H2O, CaMg(CO3)2, SiO2, feldspar, clay minerals, alpha-Fe2O3, NaNO3, and Ca(NO3)2 x 4H20. Black carbon and (NH4)2SO4 particles were observed predominantly in the finest fraction. It was not rare to detect Pb and Zn-rich particles in the 10-2.5 and 2.5-1 microm fractions collected at the southwest (SW) sampling site, when the wind was blowing from the NE sector. Most of these mixed particles probably result from the aggregation between PbSO4, PbO x PbSO4, and ZnS particles emitted by the smelters and hydroscopic mineral dust during transport in the troposphere.

Aerosols↗

PubMed1999

Fine genetic mapping of diffuse non-epidermolytic palmoplantar keratoderma to chromosome 12q11-q13: exclusion of the mapped type II keratins.

Diffuse non-epidermolytic palmoplantar keratoderma (NEPPK) belongs to the heterogeneous group of skin diseases characterized by thickening of the stratum corneum of the palms and soles (1). This autosomal dominant PPK is characterized by a diffuse pattern of palmar and plantar hyperkeratosis giving the affected areas a thickened yellowish appearance with a marked erythematous edge. Linkage of diffuse NEPPK to chromosome 12q11-q13 has been demonstrated in two independent reports (2, 3). In this study, we describe detailed haplotyping with microsatellite markers mapping to this chromosomal region in three diffuse NEPPK pedigrees from the south of England. Fine mapping of a previously identified recombination event and the identification of a common disease haplotype segregating in the three pedigrees places the diffuse NEPPK locus proximal to the type II keratin gene cluster.

Chromosome Mapping↗

PubMed1997

Myosin VIIA gene: heterogeneity of the mutations responsible for Usher syndrome type IB.

Usher syndrome is recognized as the most frequent cause of hereditary deaf-blindness. Usher syndrome type I (USH1), the most severe form of the disease, is characterized by profound congenital sensorineural deafness, constant vestibular dysfunction, and retinitis pigmentosa of prepubertal onset. This form is genetically heterogeneous and five loci (USH1A-E) have been mapped thusfar. However, only the gene responsible for USH1 B (which accounts for approximately 75% of USH1 cases) has been characterized. It encodes a long-tailed unconventional myosin, myosin VIIA, with a predicted 2215 amino acid sequence. Primers covering the complete myosin VIIA coding sequence as well as the 3' non coding sequence were designed, allowing direct sequence analysis of each of the 48 coding exons and flanking splice sites in seven patients affected by USH1. Four novel mutations were thereby identified. The possibility should now be considered of a sequence-based prenatal diagnosis in some of the families affected by this very severe form of Usher syndrome.

Base Sequence↗

PubMed1988

Isolation and characterization of complementary DNAs encoding human pregnancy-specific beta 1-glycoprotein.

Pregnancy-specific beta 1-glycoprotein (PS beta G) isolated from human placenta consists of a set of at least three glycoproteins with apparent molecular masses of 72, 64, and 54 kDa, respectively. This heterogeneity is confirmed by the detection of three nonglycosylated polypeptides of 50, 48, and 36 kDa, which can be immunoprecipitated by antiserum to placental PS beta G obtained by in vitro translation of placental poly(A)+ RNA. To examine the structural relationships between these proteins, two cDNA clones of 1912 base pairs (PSG16) and 2131 base pairs (PSG93) encoding human PS beta Gs were isolated from a human placental lambda gt11 cDNA library. The sequenced portions of these two cDNAs are identical with the exception that clone PSG93 contains an additional 86 base pairs at the end of the common 3'-coding region. This insertion could result in the generation of a PS beta G species of 419 amino acid residues instead of the 417 amino acid residues predicted by the sequence of clone PSG16. The calculated molecular masses of the two polypeptides encoded by PSG16 and PSG93 are 46.9 and 47.2 kDa, close to the size of the major nonglycosylated PS beta G of 48 kDa. The identity of proteins coded for by these cDNA clones was confirmed by comparing the predicted amino acid sequences to sequences determined from endoproteinase Lys-C peptides obtained from human placental PS beta G. Two placental PS beta G mRNAs of 2200 bases (major) and 1700 bases (minor) have been detected by Northern hybridization analysis. Primer extension and S1 nuclease mapping experiments demonstrated that PS beta G mRNAs have heterogeneous 5' termini.

Amino Acid Sequence↗

PubMed1997

Bardet-Biedl syndrome: a molecular and phenotypic study of 18 families.

The autosomal recessive disorder Bardet-Biedl syndrome is characterised by retinal degeneration, polydactyly, obesity, mental retardation, hypogenitalism, renal dysplasia, and short stature. It is heterogeneous with at least four gene loci (BBS1-4) having been mapped to date. We have studied 18 multiply affected families noting the presence of both major and minor manifestations. Using a fluorescently based PCR technique, we genotyped each family member and assigned linkage to one of the four loci. Given this degree of heterogeneity we hoped to find phenotypic differences between linkage categories. We found 44% of families linked to 11q13 (BBS1) and 17% linked to 16q21 (BBS2). Only one family was linked to 15q22 (BBS4) and none to 3p12. We conclude that BBS1 is the major locus among white Bardet-Biedl patients and that BBS3 is extremely rare. Only subtle phenotypic differences were observed, the most striking of which was a finding of taller affected offspring compared with their parents in the BBS1 category. Affected subjects in the BBS2 and 4 groups were significantly shorter than their parents. Twenty eight percent of pedigrees did not show linkage to any known locus, evidence for at least a fifth gene. We conclude that the different genes responsible for Bardet-Biedl syndrome may influence growth characteristics such as height.

Body Height↗

PubMed1993

X linked spastic paraplegia (SPG2): clinical heterogeneity at a single gene locus.

X linked hereditary spastic paraplegia is a rare condition that has been divided into two forms (the pure spastic form and the complicated form) as a function of clinical course and severity. A gene for pure hereditary spastic paraplegia (SPG2) has been mapped to the proximal long arm of the X chromosome (Xq21) by linkage to the DXS17 locus, while a gene for a complicated form of the disease has been mapped to the distal long arm by linkage to the DXS52 locus (Xq28). Here we report on the mapping of a gene for complicated hereditary spastic paraplegia to the Xq21 region by linkage to the probe S9 at the DXS17 locus (Z = 5 at theta = 0.04) in a three generation pedigree. Multipoint linkage analysis supports the distal location of the disease gene with respect to the DXYS1-DXS17 block (cen-DXYS1-DXS3-DXS17-SPG2-tel). The observation of a complicated form of spastic paraplegia mapping to Xq21 raises the difficult issue of variable phenotypic expression, allelic heterogeneity, or even close proximity of two genes for hereditary spastic paraplegia in this region. However, since our study provides clinical evidence for intrafamilial heterogeneity in complicated X linked spastic paraplegia, the present data support the hypothesis of variable clinical expression of a single gene at the SPG2 locus, as previously suggested for SPG1. Finally, we report here what we believe to be the first evidence of clinical expression in heterozygous carriers, a feature that is relevant to genetic counselling in at risk females.

Adolescent↗

PubMed2002

Structural analysis of a glycoprotein by liquid chromatography-mass spectrometry and liquid chromatography with tandem mass spectrometry. Application to recombinant human thrombomodulin.

Using recombinant human thrombomodulin (rhTM) expressed in Chinese hamster ovary (CHO) cells, we studied the structural analysis of a glycoprotein by liquid chromatography-mass spectrometry (LC-MS) and liquid chromatography with tandem mass spectrometry (LC-MS-MS). First, we analyzed the structure of both the O- and N-linked glycans in rhTM by oligosaccharide mapping using LC-MS equipped with a graphitized carbon column (GCC-LC-MS). Major O- and N-linked glycans were determined to be core 1 structure and fucosyl biantennary containing NeuAc(0-2) respectively. Next, the post-translational modifications and their heterogeneities, including the site-specific glycosylation, were analyzed by mass spectrometric peptide/glycopeptide mapping of trypsin-digested rhTM and precursor-ion scanning. Precursor-ion scanning was successful in the detection of five glycopeptides. Four N-glycosylation sites and their site-specific carbohydrate heterogeneity were determined by their mass spectra. O-Glycosylation could be estimated on the basis of its mass spectrum. We were able to identify partial beta-hydroxylation on Asn324 and Asn439, and O-linked glucose on Ser287 from the peptide/glycopeptide map and their mass spectra. We demonstrated that a sequential analysis of LC-MS and LC-MS-MS are very useful for the structural analysis of O- and N-linked glycans, polypeptides, and post-translational modifications and their heterogeneities, including site-specific glycosylation in a glycoprotein. Our method can be applied to a glycoprotein in biological samples.

Amino Acid Sequence↗

PubMed2000

LMNA, encoding lamin A/C, is mutated in partial lipodystrophy.

The lipodystrophies are a group of disorders characterized by the absence or reduction of subcutaneous adipose tissue. Partial lipodystrophy (PLD; MIM 151660) is an inherited condition in which a regional (trunk and limbs) loss of fat occurs during the peri-pubertal phase. Additionally, variable degrees of resistance to insulin action, together with a hyperlipidaemic state, may occur and simulate the metabolic features commonly associated with predisposition to atherosclerotic disease. The PLD locus has been mapped to chromosome 1q with no evidence of genetic heterogeneity. We, and others, have refined the location to a 5.3-cM interval between markers D1S305 and D1S1600 (refs 5, 6). Through a positional cloning approach we have identified five different missense mutations in LMNA among ten kindreds and three individuals with PLD. The protein product of LMNA is lamin A/C, which is a component of the nuclear envelope. Heterozygous mutations in LMNA have recently been identified in kindreds with the variant form of muscular dystrophy (MD) known as autosomal dominant Emery-Dreifuss MD (EDMD-AD; ref. 7) and dilated cardiomyopathy and conduction-system disease (CMD1A). As LMNA is ubiquitously expressed, the finding of site-specific amino acid substitutions in PLD, EDMD-AD and CMD1A reveals distinct functional domains of the lamin A/C protein required for the maintenance and integrity of different cell types.

Amino Acid Sequence↗

PubMed2006

Linkage maps for the Pacific abalone (genus Haliotis) based on microsatellite DNA markers.

This study presents linkage maps for the Pacific abalone (Haliotis discus hannai) based on 180 microsatellite DNA markers. Linkage mapping was performed using three F1 outbred families, and a composite linkage map for each sex was generated by incorporating map information from the multiple families. A total of 160 markers are placed on the consolidated female map and 167 markers on the male map. The numbers of linkage groups in the composite female and male maps are 19 and 18, respectively; however, by aligning the two maps, 18 linkage groups are formed, which are consistent with the haploid chromosome number of H. discus hannai. The female map spans 888.1 cM (Kosambi) with an average spacing of 6.3 cM; the male map spans 702.4 cM with an average spacing of 4.7 cM. However, we encountered several linkage groups that show a high level of heterogeneity in recombination rate between families even within the same sex, which reduces the precision of the consolidated maps. Nevertheless, we suggest that the composite maps are of significant potential use as a scaffold to further extend the coverage of the H. discus hannai genome with additional markers.

Animals↗

PubMed1999

The role of chimeric paired box transcription factors in the pathogenesis of pediatric rhabdomysarcoma.

Alveolar rhabdomyosarcoma (ARMS) is an aggressive pediatric soft tissue tumor with striated muscle differentiation. Chromosomal studies of these tumors identified 2;13 and 1;13 translocations. Using physical mapping and cloning strategies, we determined that t(2;13) and t(1;13) rearrange PAX3 and PAX7, which encode members of the paired box transcription factor family, and juxtapose these genes with FKHR, which encodes a novel member of the fork head transcription factor family. These translocations result in chimeric transcripts consisting of 5' PAX3 or PAX7 exons fused to 3' FKHR exons, which encode fusion proteins containing the PAX3 or PAX7 DNA-binding domain and the COOH-terminal FKHR transcriptional activation domain. In transfection studies, the PAX3-FKHR fusion activates transcription of reporter genes containing PAX DNA-binding sites, and is 10-100-fold more potent as a transcriptional activator than is wild-type PAX3. This increased function results from the insensitivity of the COOH-terminal FKHR activation domain to the inhibitory effects of NH2-terminal PAX3 domains. In addition to functional alterations, our studies demonstrated PAX3-FKHR and PAX7-FKHR overexpression resulting from two distinct mechanisms, increased transcription of PAX3-FKHR by a copy number-independent mechanism, and gene amplification of PAX7-FKHR. These findings indicate that the genetic changes in these tumors result in high levels of chimeric transcription factors that are hypothesized to inappropriately activate transcription of genes with PAX DNA-binding sites and thereby induce tumorigenic behavior. The differences in overexpression strategies suggest important differences between the mechanisms for regulating PAX3 and PAX7 expression. These differences extend to the phenotypic level, at which clinical differences have been found between the two ARMS subtypes: PAX7-FKHR tumors more often occur as localized lesions in the extremities of younger patients and are associated with longer event-free survival as compared to PAX3-FKHR tumors. Therefore, the clinical heterogeneity within the ARMS category is associated with genetic heterogeneity. Further analysis of the transcriptional function, regulation of expression, and phenotypic effects will help to elucidate the action of these fusion products and the biological basis of the clinical heterogeneity.

Child↗

PubMed1996

Mapping of a second locus for lamellar ichthyosis to chromosome 2q33-35.

Lamellar ichthyosis (LI) is an inherited autosomal recessive disorder of cornification. It was recently demonstrated to result from deleterious mutations in the transglutaminase 1 (TGM1) gene. However, the disease was shown to be genetically heterogeneous, since some families were found to be unlinked to TGM1. Homozygosity mapping on three consanguinous families originating from Morocco shows (i) absence of linkage with TGM1 and other regions of the genome containing genes involved in cornification, and (ii) location of a second disease-causing gene on chromosome 2q33-35. A maximum two-point lodscore of 7.60 was obtained with D2S157 for theta = 0. The analysis of recombination events places the gene within a 7-8 cM interval. Additional consanguinous pedigrees were also demonstrated to be unlinked both to TGM1 and to 2q33-35, suggesting the existence of at least a third disease-causing gene.

Chromosome Mapping↗

PubMed2007

An investigation of the effects of endometriosis on the proteome of human eutopic endometrium: a heterogeneous tissue with a complex disease.

The pathogenesis of endometriosis includes the proliferation of heterogeneous endometrial cells and their invasion into ectopic sites within the peritoneal cavity. This may be due to abnormalities of the eutopic endometrium itself, predisposing the cells to survive and implant ectopically. We investigated the applicability of 2-DE gels and peptide mass mapping to identify candidate endometrial proteins with a role in endometriosis. Despite the heterogeneous nature of endometrium, our results show that combining the analysis of 2-DE gels and peptide mass mapping yields consistent data. We identified dysregulated proteins in women with endometriosis which included: (i) molecular chaperones including heat shock protein 90 and annexin A2, (ii) proteins involved in cellular redox state, such as peroxiredoxin 2, (iii) proteins involved in protein and DNA formation/breakdown, including ribonucleoside-diphosphate reductase, prohibitin and prolyl 4-hydroxylase, and (iv) secreted proteins, such as apolipoprotein A1. These proteins have functions which suggest that they could play a role in the pathogenesis of endometriosis. This study demonstrated that 2-DE gel analysis and mass spectroscopic protein identification are suitable for the identification of proteins with candidate associations with endometriosis. These techniques should be used on a larger scale to identify endometriosis-related proteins, thus improving the understanding of this complex disease.

Adult↗

PubMed2002

CFEOM1, the classic familial form of congenital fibrosis of the extraocular muscles, is genetically heterogeneous but does not result from mutations in ARIX.

BACKGROUND: To learn about the molecular etiology of strabismus, we are studying the genetic basis of 'congenital fibrosis of the extraocular muscles' (CFEOM). These syndromes are characterized by congenital restrictive ophthalmoplegia affecting muscles in the oculomotor and trochlear nerve distribution. Individuals with the classic form of CFEOM are born with bilateral ptosis and infraducted globes. When all affected members of a family have classic CFEOM, we classify the family as a CFEOM1 pedigree. We have previously determined that a CFEOM1 gene maps to the FEOM1 locus on chromosome 12cen. We now identify additional pedigrees with CFEOM1 to determine if the disorder is genetically heterogeneous and, if so, if any affected members of CFEOM1 pedigrees or sporadic cases of classic CFEOM harbor mutations in ARIX, the CFEOM2 disease gene. RESULTS: Eleven new CFEOM1 pedigrees were identified. All demonstrated autosomal dominant inheritance, and nine were consistent with linkage to FEOM1. Two small CFEOM1 families were not linked to FEOM1, and both were consistent with linkage to FEOM3. We screened two CFEOM1 families consistent with linkage to FEOM2 and 5 sporadic individuals with classic CFEOM and did not detect ARIX mutations. CONCLUSIONS: The phenotype of two small CFEOM1 families does not map to FEOM1, establishing genetic heterogeneity for this disorder. These two families may harbor mutations in the FEOM3 gene, as their phenotype is consistent with linkage to this locus. Thus far, we have not identified ARIX mutations in any affected members of CFEOM1 pedigrees or in any sporadic cases of classic CFEOM.

Female↗

PubMed1995

Physical mapping of the holoprosencephaly critical region in 18p11.3.

Holoprosencephaly (HPE) is a common developmental defect that results in a spectrum of craniofacial malformations. HPE is genetically heterogeneous, some cases being associated with deletions of the short arm of chromosome 18. In order to map the putative HPE gene located on 18p (HPE4) more precisely, six patients with various cytogenetic 18p deletions and clinical features of HPE have been characterized by using a combination of somatic cell hybrid analysis and FISH. By using a set of 27 chromosome 18p-specific markers, the deletion in each patient was characterized. The HPE minimal critical region on 18p was defined on a molecular level, localizing the HPE4 gene to 18p11.3.

Child↗