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The distribution of HLA antigens in Italy.

Human histocompatibility (HLA) gene frequencies were studied in the Italian population. A random sample of healthy individuals born in several Italian regions and provinces was studied to estimate HLA-A, -B, -C and -DR gene frequencies using the maximum likelihood method. The goodness of fit to Hardy-Weinberg proportions was evaluated by the likelihood ratio statistics. Different Italian regions and provinces show significant differences in the HLA alleles, providing further evidence for the genetic heterogeneity in the Italian population. This heterogeneity is also displayed by a synthetic geographical representation which uses colour to map the most informative gene differences. Statistically significant gametic associations between HLA-A, -B, -C and -DR loci are reported. The difference between northern and southern Italy and between continental Italy and Sardegna is clearly shown also by their heterogeneous linkage disequilibria.

Alleles↗
PubMed1997

A new locus for non-syndromal, autosomal recessive, sensorineural hearing loss (DFNB16) maps to human chromosome 15q21-q22.

Non-syndromal, recessive deafness (NSRD) is the most common form of inherited deafness or hearing impairment in humans. NSRD is genetically heterogeneous and it has been estimated that as many as 35 different loci may be involved. We report the mapping of a novel locus for autosomal recessive, non-syndromal deafness (DFNB16) in three consanguineous families originating from Pakistan and the Middle East. Using multipoint analysis (HOMOZ/MAPMAKER) a maximum combined lod score of 6.5 was obtained for the interval D15S1039-D15S123. Recombination events and haplotype analysis define a 12-14 cM critical region between the markers D15S1039 and D15S155 on chromosome 15q15-q21.

Chromosome Mapping↗
PubMed1992

A linkage map of 10 loci flanking the Marfan syndrome locus on 15q: results of an International Consortium study.

Members of an International Consortium for Linkage Analysis of the Marfan Syndrome (MFS1) have pooled data for joint analysis in an attempt to determine the precise location of the MFS1 gene and the order of 10 DNA markers on 15q. Five laboratories performed a total of 2111 genotypes in 22 families consisting of 225 affected and 248 normal subjects. For each marker a mean of 98 meioses was informative. D15S48 and D15S1 were identified as the closest linked markers with 99% upper confidence intervals of 12% and 13% respectively. We have used the CRI-MAP program to construct the most likely order as: D15S24-D15S25-D15S1-MFS1-D15S48-D15S49+ ++-(D15S45/S51)-(D15S29/S38). Placement of D15S2 in relation to -D15S1-D15S48- cannot be determined with certainty. The genetic map of these markers extends 53.6 cM in males and 65.0 cM in females with a sex averaged map of 60.7 cM. The sex difference was statistically significant (p = 0.005). Linkage heterogeneity between 22 MFS1 families was documented (p = 0.009) necessitating the exclusion of one family from the analysis. However, comparison of the remaining 21 families for two point and multipoint lod scores showed no evidence for linkage heterogeneity of the MFS1 locus.

Chromosome Mapping↗
PubMed1984

Characterization of heterogeneous nuclear RNA-protein complexes in vivo with monoclonal antibodies.

Exposure of cells to UV light of sufficient intensity brings about cross-linking of RNA to proteins which are in direct contact with it in vivo. The major [35S]methionine-labeled proteins which become cross-linked to polyadenylated heterogeneous nuclear RNA in HeLa cells have molecular weights of 120,000 (120K), 68K, 53K, 43K, 41K, 38K, and 36K. Purified complexes of polyadenylated RNA with proteins obtained by UV cross-linking in intact cells were used to immunize mice and generate monoclonal antibodies to several of these proteins. Some properties of three of the proteins, 41K, 43K, and 120K, were characterized with these antibodies. The 41K and 43K polypeptides are highly related. They were recognized by the same antibody (2B12) and have identical isoelectric points (pl = 6.0 +/- 0.2) but different partial peptide maps. The 41K and 43K polypeptides were part of the 40S heterogeneous nuclear ribonucleoprotein particle and appear to correspond to the previously described C proteins (Beyer et al., Cell II:127-138, 1977). A different monoclonal antibody (3G6) defined a new major heterogeneous ribonucleoprotein of 120K. The 41K, 43K, and 120K polypeptides were associated in vivo with both polyadenylated and non-polyadenylated nuclear RNA, and all three proteins were phosphorylated. The monoclonal antibodies recognized similar proteins in human and monkey cells but not in several other vertebrates. Immunofluorescence microscopy demonstrated that these proteins are segregated to the nucleus, where they are part of a fine particulate nonnucleolar structure. In cells extracted in situ with nonionic detergent, all of the 41K and 43K polypeptides were associated with the nucleus at salt concentrations up to 0.5 M NaCl, whereas the 120K polypeptide was completely extracted at this NaCl concentration. A substantial fraction of the 41K and 43K polypeptides (up to 40%) was retained with a nuclear matrix--a structure which is resistant to digestion with DNase I and to extraction by 2 M NaCl, but the 41K and 43K polypeptides were quantitatively removed at 0.5 M NaCl after digestion with RNase.

Animals↗
PubMed1994

Genetic heterogeneity of familial hemiplegic migraine.

Familial hemiplegic migraine (FHM) is an autosomal dominant variety of migraine with aura. We previously mapped a gene responsible for this disorder to the short arm of chromosome 19, within a 30-cM interval bracketed by D19S216 and D19S215. Linkage analysis conducted on two large pedigrees did not show any evidence of heterogeneity, despite their clinical differences due to the presence, in one family, of cerebellar ataxia and nystagmus. Herein we report linkage data on seven additional FHM families including another one with cerebellar ataxia. Analysis was conducted with a set of seven markers spanning the D19S216-D19S215 interval. Two-point and multipoint lod score analyses as well as HOMOG testing provided strong evidence for genetic heterogeneity. Strong evidence of linkage was obtained in two families and of absence of linkage in four families. The posterior probability of being of the linked type was > .95 in the first two families and < .01 in four other ones. It was not possible to draw any firm conclusion for the last family. Thus, within the nine families so far tested, four were linked, including those with associated cerebellar ataxia. We could not find any clinical difference between the pure FHM families regardless of whether they were linked. In addition to the demonstration of genetic heterogeneity of FHM, this study also allowed us to establish that the most likely location of the gene was within an interval of 12 cM between D19S413 and D19S226.

Ataxia↗
PubMed1999

Delineation of the critical interval of Bardet-Biedl syndrome 1 (BBS1) to a small region of 11q13, through linkage and haplotype analysis of 91 pedigrees.

Bardet-Biedl syndrome (BBS) is a genetically heterogeneous recessive disease characterized primarily by atypical retinitis pigmentosa, obesity, polydactyly, hypogenitalism, and mental retardation. Despite the presence of at least five loci in the human genome, on chromosomes 2q, 3p, 11q, 15q and 16q, as many as 50% of the mutations appear to map to the BBS1 locus on 11q13. The recessive mode of inheritance and the genetic heterogeneity of the syndrome, as well as the inability to distinguish between different genetic loci by phenotypic analyses, have hindered efforts to delineate the 11q13 region as a first step toward cloning the mutated gene. To circumvent these difficulties, we collected a large number of BBS pedigrees of primarily North American and European origin and performed genetic analysis, using microsatellites from all known BBS genomic regions. Heterogeneity analysis established a 40.5% contribution of the 11q13 locus to BBS, and haplotype construction on 11q-linked pedigrees revealed several informative recombinants, defining the BBS1 critical interval between D11S4205 and D11S913, a genetic distance of 2.9 cM, equivalent to approximately 2.6 Mb. Loss of identity by descent in two consanguineous pedigrees was also observed in the region, potentially refining the region to 1.8 Mb between D11S1883 and D11S4944. The identification of multiple recombinants at the same position forms the basis for physical mapping efforts, coupled with mutation analysis of candidate genes, to identify the gene for BBS1.

Bardet-Biedl Syndrome↗
PubMed1994

A gene for autosomal recessive limb-girdle muscular dystrophy maps to chromosome 2p.

The limb-girdle muscular dystrophies are a clinically and genetically heterogeneous group of disorders. We have studied two large inbred families of different ethnic origin and excluded linkage to LGMD2 on chromosome 15q and SCARMD on chromosome 13. Proceeding to a genomic linkage search, we have now identified linkage to markers D2S134 and D2S136 on chromosome 2p (maximum lod score 3.57 at zero recombination). The phenotype in the two families was similar, with onset in the pelvic girdle musculature in the late teens and usually relatively slow progression. This work identifies a second locus for autosomal recessive limb-girdle muscular dystrophy.

Adolescent↗
PubMed2003

Intratumoral heterogeneity of genetic changes in primary colorectal carcinomas with metastasis.

PURPOSE: To elucidate the intratumoral distribution of genetic changes, surgically resected colorectal carcinomas were investigated regarding their loss of heterozygosity in the regions of tumor suppressor genes and the mutation of ras genes. METHODS: Full-thickness fresh tumor slices from 23 colorectal carcinomas were removed and divided into multiple specimens, which were then submitted separately for DNA and histopathological analyses. The loss of heterozygosity was analyzed in 23 primary carcinomas and 9 metastasized carcinomas by the use of restriction fragment-length polymorphism markers on chromosome 1p, 5q, 17p, 18q, and 22q. RESULTS: Intratumoral heterogeneity was identified in 11 of 23 primary carcinomas (47.8%) and we could successfully map the regional genetic variation. In both stages I and II, 1 of 5 cases (20%); in stage III, 3 of 6 cases (50%); and in stage IV, 6 of 7 cases (85.7%) were heterogeneous. With respect to venous invasion positive primary carcinomas, hepatic metastasis occurred in 75% (6/8) of the heterogeneous carcinomas, whereas hepatic metastasis occurred in only 12.5% (1/8) of homogeneous carcinomas. CONCLUSION: The present results suggest that the existence of intratumoral heterogeneity, which may reflect genetic instability, may thus play a role in the enhancement of aggressive progression and the metastasis of colorectal carcimomas.

Adult↗
PubMed1996

Refined mapping of a gene for split hand-split foot malformation (SHFM3) on chromosome 10q25.

Split hand-split foot malformation (SHFM) is a genetically heterogeneous limb developmental defect characterised by the absence of digital rays and syndactyly of the remaining digits. Three disease loci have recently been mapped to chromosomes 7q21 (SHFM1), Xq26 (SHFM2), and 10q25 respectively (SHFM3). We report the mapping of SHFM3 to chromosome 10q25 in two large SHFM families of French ancestry (Zmax for the combined families = 6.62 at theta = 0 for marker AFM249wc5 at locus D10S222). Two recombinant events reduced the critical region to a 9 cM interval (D10S1709-D10S1663) encompassing several candidate genes including a paired box gene PAX2 (Zmax = 5.35 at theta = 0). The fibroblast growth factor 8 (FGF 8), the retinol binding protein (RBP4), the zinc finger protein (ZNF32), and the homeobox genes HMX2 and HOX11 are also good candidates by both their position and their function.

Chromosome Mapping↗
PubMed2001

A new locus for autosomal dominant Charcot-Marie-Tooth disease type 2 (CMT2F) maps to chromosome 7q11-q21.

Charcot-Marie-Tooth disease (CMT) constitutes a genetically heterogeneous group of inherited motor and sensory peripheral neuropathies. The axonal type of CMT is designated CMT type 2 (CMT2). Four loci for autosomal dominant CMT2 have been reported so far. Only in CMT2E, linked to chromosome 8p21, disease-causing mutations in the gene for neurofilament light chain (NEFL) were identified. In this study we report a multigenerational Russian family with autosomal dominant CMT2 and assign the locus to chromosome 7q11-q21. The CMT2 neuropathy in this family represents a novel genetic entity designated CMT2F.

Adolescent↗
PubMed1995

Genetic heterogeneity of heart-hand syndromes.

BACKGROUND: Heart-hand syndromes compose a class of combined congenital cardiac and limb deformities. The proto-typical heart-hand disorder is Holt-Oram syndrome, which is characterized by cardiac septation defects and radial ray limb deformity. We have recently mapped the Holt-Oram syndrome gene defect to the long arm of human chromosome 12 in two families. The role of this disease locus in the pathogenesis of related conditions such as heart-hand syndrome type III (cardiac conduction disease accompanied by skeletal malformations) or familial atrial septal defects is unknown. METHODS AND RESULTS: Clinical evaluations and genetic linkage analyses were performed in five additional kindreds with Holt-Oram syndrome and also in one kindred with heart-hand syndrome type III and one kindred with familial atrial septal defect and conduction disease. Holt-Oram syndrome in all five kindreds mapped to chromosome 12q2. These studies and previous data provide odds of greater than 10(25):1 that the Holt-Oram syndrome disease gene is at chromosome 12q2. In contrast, neither the phenotypically similar disorder heart-hand syndrome type III nor the locus responsible for a familial atrial septal defect with atrioventricular block maps to chromosome 12q2. CONCLUSIONS: We demonstrate that heart-hand syndromes are genetically heterogeneous. Conditions that clinically appear to be partial phenocopies of Holt-Oram syndrome arise from distinct disease genes.

Chromosomes, Human, Pair 12↗
PubMed2005

Heterogeneity: GAW Group 15.

This paper summarizes the contributions to Group 15 of Genetic Analysis Workshop (GAW) 14, which focused on methods for dealing with heterogeneity in linkage and association analysis. A variety of methods were employed, ranging from manipulation of the phenotype and/or identification of endophenotypes prior to analysis, to statistical methods allowing for heterogeneity in the analysis of simple dichotomous phenotypes as provided with the data. Overall, it was difficult to draw broad conclusions from these applications. Groups that focused on the simulated data had fairly consistent success in mapping the major genes (but not the two minor genes). However, this appeared to be the case regardless of whether heterogeneity was explicitly modeled, either at the phenotypic or statistical level, with relatively crude statistical methods applied to the simulated simple dichotomous trait Kofendrerd personality disorder also enjoying considerable success.

Alcoholism↗
PubMed2002

Further evidence for a fourth gene causing X-linked pure spastic paraplegia.

X-linked hereditary spastic paraplegias (HSPs) present with two distinct phenotypes: pure and complicated. The pure form is characterized by slowly progressive weakness and spasticity of the lower limbs, whereas the complicated forms have additional features (optic neuropathy, retinopathy, extrapyramidal disturbance, dementia, epilepsy, ataxia, ichthyosis, mental retardation, and deafness). Three X-linked loci have been identified for the complicated HSP, while mutations in the proteolipid gene (PLP) (locus SPG2) were implicated in both pure and complicated forms. The absence of identified mutations in the PLP gene in families with both complicated and pure HSP, linked to the SPG2 locus, suggests the existence of another gene in close proximity. We had previously reported a large pedigree with an X-linked form of pure HSP affecting 24 males [Zatz et al., 1976: J Med Genet 13:217-222]. Here, we present the results of linkage analysis in 19 members of this Brazilian family with markers in or near the PLP locus. Positive LOD scores were obtained with markers at the PLP locus (Zmax = 2.41 at Theta = 0); however, no mutation was found in the coding region of PLP, the intron-exon boundaries, or part of the promoter region. The possibility of a duplication of the PLP gene was also excluded. These results suggest either that there is another X-linked gene in close proximity to the PLP gene or that a novel mutation in the noncoding regions of the PLP gene may cause the disease in this family.

Adolescent↗
PubMed1994

Pericentromeric genes for non-specific X-linked mental retardation (MRX).

Extensive linkage analyses in three families with non-specific X-linked mental retardation (MRX) have localized the gene in each family to the pericentromeric region of the chromosome. The MRX17 gene is localized with a peak lod of 2.41 (theta = 0.0) with the trinucleotide repeat polymorphism at the androgen receptor (AR) gene locus. This gene lies in the interval between the markers DXS255 and DXS990, as defined by recombinants. The MRX18 gene maps to the interval between the markers DXS538 and DXS1126, with a peak lod score of 2.01 (theta = 0.0) at the PFC gene locus. In the third family (Family E) with insufficient informative meioses for assignment of an MRX acronym, the maximum lod score is 1.8 at a recombination fraction of zero for several marker loci between DXS207 and DXS426. Exclusions from the regions of marker loci spanning Xq support the localization of the MRX gene in Family E to the pericentromeric region. Localizations of these and other MRX genes have determined that MRX2 and MRX19 map to distal Xp, MRX3, and MRX6 map to distal Xq, whilst the majority cluster in the pericentromeric region. In addition, we confirm that there are at least two distinct MRX genes near the centromere as delineated by the non-overlapping regional localizations of MRX17 and MRX18. Determination of these non-overlapping localizations is currently the only means of classifying non-syndromal forms of mental retardation and determining the minimum number of MRX loci.

Adolescent↗
PubMed2005

Marinesco-Sjögren syndrome in a male with mild dysmorphism.

Marinesco-Sjogren syndrome (MSS) is a rare, autosomal recessive disorder comprising cataracts, cerebellar ataxia caused by cerebellar hypoplasia, mild to moderate mental retardation, neuromuscular weakness, short stature, hypergonadotrophic hypogonadism, and skeletal anomalies. The syndrome was recently mapped to chromosome 5q31, but there is evidence for genetic heterogeneity, and no gene has been identified. We report a 5-year-old male with cataracts, ataxia, a progressive cerebellar atrophy, developmental delay, seizures, hypotonia, and a sensorimotor neuropathy consistent with many cases of MSS. He also had mild craniofacial dysmorphism consisting of hypertrichosis and synophrys, deep-set eyes with epicanthic folds, a flat philtrum, a high palate, short thumbs, and a wide sandal gap between the first and second toes. Skeletal findings included an increased kyphosis. We reviewed the literature on MSS to determine if craniofacial dysmorphism and the presence of neuropathy and/or myopathy would prove to be diagnostically useful in this phenotypically heterogeneous condition. The majority of cases of MSS do not have craniofacial dysmorphism, but other cases have been reported with features such as ptosis or a myopathic facies that are likely to reflect the underlying myopathic or neuromuscular processes in MSS.

Abnormalities, Multiple↗
PubMed2006

Split-hand/split-foot malformation 3 (SHFM3) at 10q24, development of rapid diagnostic methods and gene expression from the region.

Split-hand/split-foot malformation (SHFM, also called ectrodactyly) is a clinically variable and genetically heterogeneous group of limb malformations. Several SHFM loci have been mapped, including SHFM1 (7q21), SHFM2 (Xq26), SHFM3 (10q24), SHFM4 (3q27) and SHFM5 (2q31). To date, mutations in a gene (TP63) have only been identified for SHFM4. SHFM3 has been shown by pulsed-field gel electrophoresis to be caused by an approximately 500 kb DNA rearrangement at 10q24. This region contains a number of candidate genes for SHFM3, though which gene(s) is (are) involved in the pathogenesis of SHFM3 is not known. Our aim in this study was to improve the diagnosis of SHFM3, and to begin to understand which genes are involved in SHFM3. Here we show, using two different techniques, FISH and quantitative PCR that SHFM3 is caused by a minimal 325 kb duplication containing only two genes (BTRC and POLL). The data presented provide improved methods for diagnosis and begin to elucidate the pathogenic mechanism of SHFM3. Expression analysis of 13 candidate genes within and flanking the duplicated region shows that BTRC (present in three copies) and SUFU (present in two copies) are overexpressed in SHFM3 patients compared to controls. Our data suggest that SHFM3 may be caused by overexpression of BTRC and SUFU, both of which are involved in beta-catenin signalling.

Chromosomes, Human, Pair 10↗
PubMed2004

Effects of skull thickness, anisotropy, and inhomogeneity on forward EEG/ERP computations using a spherical three-dimensional resistor mesh model.

Bone thickness, anisotropy, and inhomogeneity have been reported to induce important variations in electroencephalogram (EEG) scalp potentials. To study this effect, we used an original three-dimensional (3-D) resistor mesh model described in spherical coordinates, consisting of 67,464 elements and 22,105 nodes arranged in 36 different concentric layers. After validation of the model by comparison with the analytic solution, potential variations induced by geometric and electrical skull modifications were investigated at the surface in the dipole plane and along the dipole axis, for several eccentricities and bone thicknesses. The resistor mesh permits one to obtain various configurations, as local modifications are introduced very easily. This has allowed several head models to be designed to study the effects of skull properties (thickness, anisotropy, and heterogeneity) on scalp surface potentials. Results show a decrease of potentials in bone, depending on bone thickness, and a very small decrease through the scalp layer. Nevertheless, similar scalp potentials can be obtained using either a thick scalp layer and a thin skull layer, and vice versa. It is thus important to take into account skull and scalp thicknesses, because the drop of potential in bone depends on both. The use of three different layers for skull instead of one leads to small differences in potential values and patterns. In contrast, the introduction of a hole in the skull highly increases the maximum potential value (by a factor of 11.5 in our case), because of the absence of potential drop in the corresponding volume. The inverse solution without any a priori knowledge indicates that the model with the hole gives the largest errors in both position and dipolar moment. Our results indicate that the resistor mesh model can be used as a robust and user-friendly simulation tool in EEG or event-related potentials. It makes it possible to build up real head models directly from anatomic magnetic resonance imaging without tessellation, and is able to take into account head heterogeneities very simply by changing volume elements conductivity. Hum. Brain Mapping 21:84-95, 2004.

Anisotropy↗