Localization of the human glucagon gene (GCG) to chromosome segment 2q36----37

Hybridization of a 3H-labeled bovine glucagon cDNA plasmid to human metaphase chromosomes revealed significant labeling of the distal portion of the long arm of chromosome 2. A large portion (37%) of the cells analyzed exhibited labeling of the 2. A significant percentage (40%) of the labeled sites on the 2 were in segment 2q36----37. Therefore, the human glucagon gene (GCG), was assigned to this segment. Localization of the glucagon gene, whose chromosomal assignment was previously not known, demonstrates the general applicability of in situ hybridization as a powerful gene mapping technique.     

Mapping of the kinesin-related gene ATSV to chromosome 2q37

The human ATSV (axonal transporter of synaptic vesicles) gene encodes an anterograde axonal motor transport protein and demonstrates homology to the kinesin gene family in several species. The human ATSV gene was mapped to chromosome 2q37 by screening of a human/rodent somatic cell hybrid panel by the polymerase chain reaction and by fluorescent in situ hybridization analysis using genomic and cDNA clones. Received: 12 November 1998 / Accepted: 18 December 1998     

High-density genome scan in Crohn disease shows confirmed linkage to chromosome 14q11-12

Epidemiological studies have shown that genetic factors contribute to the pathogenesis of the idiopathic inflammatory bowel diseases (IBD), Crohn disease (CD) and ulcerative colitis (UC). Recent genome scans and replication studies have identified replicated linkage between CD and a locus on chromosome 16 (the IBD1 locus), replicated linkage between IBD (especially UC) and a locus on chromosome 12q (the IBD2 locus), and replicated linkage between IBD (especially CD) and a locus on chromosome 6p (the IBD3 locus). Since the estimated locus-specific lambdas values for the regions of replicated linkage do not account for the overall lambdas in CD, and since the published genome scans in IBD show at least nominal evidence for linkage to regions on all but two chromosomes, we performed an independent genome scan using 751 microsatellite loci in 127 CD-affected relative pairs from 62 families. Single-point nonparametric linkage analysis using the GENEHUNTER-PLUS program shows evidence for linkage to the adjacent D14S261 and D14S283 loci on chromosome 14q11-12 (LOD = 3.00 and 1.70, respectively), and the maximal multipoint LOD score is observed at D14S261 (LOD = 3.60). In the multipoint analysis, nominal evidence for linkage (P<.05) is observed near D2S117 (LOD = 1.25), near D3S3045 (LOD = 1.31), between D7S40 and D7S648 (LOD = 0.91), and near D18S61 (LOD = 1.15). Our finding of significant linkage to D14S261 and the finding of suggestive linkage to the same locus in an independent study (multipoint LOD = 2.8) satisfies criteria for confirmed linkage, so we propose that the region of interest on chromosome 14q11-12 should be designated the IBD4 locus.     

Paroxysmal dystonic choreoathetosis: tight linkage to chromosome 2q.

Paroxysmal dystonic choreoathetosis (PDC) is characterized by attacks of involuntary movements that last up to several hours and occur at rest both spontaneously and following caffeine or alcohol consumption. We analyzed a Polish-American kindred with autosomal dominant PDC and identified tight linkage between the disorder and microsatellite markers on chromosome 2q (maximum two-point LOD score 4.77; recombination fraction 0). Our results clearly establish the existence of a locus for autosomal dominant PDC on distal chromosome 2q. The fact that three other paroxysmal neurological disorders (periodic ataxia with myokymia and hypo- and hyperkalemic periodic paralysis) are due to mutation in ion-channel genes raises the possibility that PDC is also due to an ion-channel gene mutation. It is noteworthy that a cluster of sodium-channel genes is located on distal chromosome 2q, near the PDC locus. Identifying the PDC locus on chromosome 2q will facilitate discovery of the PDC gene and enable investigators to determine whether PDC is genetically homogeneous and whether other paroxysmal movement disorders are also genetically linked to the PDC locus.     

Genetic linkage of Paget disease of the bone to chromosome 18q.

Paget disease is a common bone disease characterized by abnormal osteoclasts that are large, multinucleated, and overactive and that contain paramyxovirus-like nuclear inclusions. There is evidence for a major genetic component to Paget disease, with up to 40% of patients having affected first-degree relatives; however, the locus (loci) and gene(s) involved are unknown. Another bone disorder, familial expansile osteolysis (FEO), although extremely rare, also is characterized by similar osteoclast abnormalities but has an earlier age at onset and a more aggressive clinical progression. The causative gene for FEO has been localized to a region of human chromosome 18q. On the basis of the presence of similar clinical findings and of viral-like nuclear inclusions in osteoclasts, we hypothesized that FEO and Paget disease are allelic versions of the same locus. Therefore, a large kindred with a high incidence of Paget disease was examined to determine if Paget disease was linked to genetic markers in the same region of chromosome 18 as that for FEO. Our analysis yielded a two-point LOD score of 3.40, with the genetic marker D18S42, a marker tightly linked to the FEO locus. This demonstrates that the gene(s) responsible for FEO and that for Paget disease are either closely linked or the same locus.     

A second gene for otosclerosis, OTSC2, maps to chromosome 7q34-36

Otosclerosis due to abnormal bone homeostasis of the otic capsule is a frequent cause of hearing loss in adults. Usually, the hearing loss is conductive, resulting from fixation of the stapedial footplate, which prevents normal ossicular vibration in response to sound. An additional type of sensorineural hearing loss may be caused by otosclerotic damage to the cochlea. The etiology of the disease is unknown, and both environmental and genetic factors have been implicated. Autosomal dominant inheritance with reduced penetrance has been proposed, but large families are extremely rare. To elucidate the pathogenesis of the disease, identification of the responsible genes is essential. In this study, we completed linkage analysis in a Belgian family in which otosclerosis segregates as an autosomal dominant disease. After excluding linkage to a known locus on chromosome 15 (OTSC1), we found linkage on chromosome 7q, with a multipoint LOD score of 3.54. Analysis of key recombinant individuals maps this otosclerosis locus (OTSC2) to a 16-cM interval on chromosome 7q34-36 between markers D7S495 and D7S2426.     

The Bjornstad syndrome (sensorineural hearing loss and pili torti) disease gene maps to chromosome 2q34-36.

We report that the Bjornstad syndrome gene maps to chromosome 2q34-36. The clinical association of sensorineural hearing loss with pili torti (broken, twisted hairs) was described >30 years ago by Bjornstad; subsequently, several small families have been studied. We evaluated a large kindred with Bjornstad syndrome in which eight members inherited pili torti and prelingual sensorineural hearing loss as autosomal recessive traits. A genomewide search using polymorphic loci demonstrated linkage between the disease gene segregating in this kindred and D2S434 (maximum two-point LOD score = 4.98 at theta = 0). Haplotype analysis of recombination events located the disease gene in a 3-cM region between loci D2S1371 and D2S163. We speculate that intermediate filament and intermediate filament-associated proteins are good candidate genes for causing Bjornstad syndrome.     

Significant linkage to airway responsiveness on chromosome 12q24 in families of children with asthma in Costa Rica

Although asthma is a major public health problem in certain Hispanic subgroups in the United States and Latin America, only one genome scan for asthma has included Hispanic individuals. Because of small sample size, that study had limited statistical power to detect linkage to asthma and its intermediate phenotypes in Hispanic participants. To identify genomic regions that contain susceptibility genes for asthma and airway responsiveness in an isolated Hispanic population living in the Central Valley of Costa Rica, we conducted a genome-wide linkage analysis of asthma (n = 638) and airway responsiveness (n = 488) in members of eight large pedigrees of Costa Rican children with asthma. Nonparametric multipoint linkage analysis of asthma was conducted by the NPL-PAIR allele-sharing statistic, and variance component models were used for the multipoint linkage analysis of airway responsiveness as a quantitative phenotype. All linkage analyses were repeated after exclusion of the phenotypic data of former and current smokers. Chromosome 12q showed some evidence of linkage to asthma, particularly in nonsmokers (P < 0.01). Among nonsmokers, there was suggestive evidence of linkage to airway responsiveness on chromosome 12q24.31 (LOD = 2.33 at 146 cM). After genotyping 18 additional short-tandem repeat markers on chromosome 12q, there was significant evidence of linkage to airway responsiveness on chromosome 12q24.31 (LOD = 3.79 at 144 cM), with a relatively narrow 1.5-LOD unit support interval for the observed linkage peak (142–147 cM). Our results suggest that chromosome 12q24.31 contains a locus (or loci) that influence a critical intermediate phenotype of asthma (airway responsiveness) in Costa Ricans. This work was supported by grants HL04370 and HL66289 from the National Institutes of Health.     

Genetic susceptibility to pre-eclampsia and chromosome 7q36

Pre-eclampsia is the most common serious medical disorder of human pregnancy. The human endothelial cell nitric oxide synthase (eNOS) gene is a candidate for pre-eclampsia/eclampsia (PE/E) susceptibility. A linkage study was performed on Australian PE/E families using 25 microsatellite markers from chromosome 7, one of which (eNOS-CA) resides within the eNOS gene. No significant linkage was found for the eNOS-CA marker using either parametric or non-parametric analysis. However, D7S 1805 from the eNOS gene region on 7q36, gave a suggestion of linkage using parametric analysis (maximum LOD score =2.143 at theta=0.14) and non-parametric APM analysis (T1/sqrt(p)=3.53; P=0.002). Further, an association study was performed on unrelated PE/E cases and controls from both Chinese and Australian populations to test for a relationship between the eNOS gene and PE/E. No association was found between the eNOS-CA marker and PE/E in either population. However, there was a significant difference in the allelic distribution of eNOS-CA between the two ethnic groups. The linkage results support the possibility that a susceptibility locus for pre-eclampsia resides in the 7q36 region, however, there is no definitive evidence to support the notion that the eNOS gene itself is responsible for susceptibility to pre-eclampsia.     

Chorea-acanthocytosis: genetic linkage to chromosome 9q21.

Chorea-acanthocytosis (CHAC) is a rare autosomal recessive disorder characterized by progressive neurodegeneration and unusual red-cell morphology (acanthocytosis), with onset in the third to fifth decade of life. Neurological impairment with acanthocytosis (neuroacanthocytosis) also is seen in abetalipoproteinemia and X-linked McLeod syndrome. Whereas the molecular etiology of McLeod syndrome has been defined (Ho et al. 1994), that of CHAC is still unknown. In the absence of cytogenetic rearrangements, we initiated a genomewide scan for linkage in 11 families, segregating for CHAC, who are of diverse geographical origin. We report here that the disease is linked, in all families, to a 6-cM region of chromosome 9q21 that is flanked by the recombinant markers GATA89a11 and D9S1843. A maximum two-point LOD score of 7.1 (theta = .00) for D9S1867 was achieved, and the linked region has been confirmed by homozygosity-by-descent, in offspring from inbred families. These findings provide strong evidence for the involvement of a single locus for CHAC and are the first step in positional cloning of the disease gene.     

Localization of a gene for syndactyly type 1 to chromosome 2q34-q36

Syndactyly type 1 (SD1) is an autosomal dominant limb malformation characterized in its classical form by complete or partial webbing between the third and fourth fingers and/or the second and third toes. After exclusion of a candidate region previously identified for syndactyly type 2 (synpolydactyly), we performed a genomewide linkage analysis in a large German pedigree. We found evidence for linkage of SD1 to polymorphic markers on chromosome 2q34-q36, with a maximum LOD score of 12.40 for marker D2S301. Key recombination events in affected individuals defined a 9.4-cM region between markers D2S2319 and D2S344. The identification of the responsible gene will give further insights into the molecular basis of limb development.     

Genomewide significant linkage to migrainous headache on chromosome 5q21

Familial typical migraine is a common, complex disorder that shows strong familial aggregation. Using latent-class analysis (LCA), we identified subgroups of people with migraine/severe headache in a community sample of 12,245 Australian twins (60% female), drawn from two cohorts of individuals aged 23-90 years who completed an interview based on International Headache Society criteria. We report results from genomewide linkage analyses involving 756 twin families containing a total of 790 independent sib pairs (130 affected concordant, 324 discordant, and 336 unaffected concordant for LCA-derived migraine). Quantitative-trait linkage analysis produced evidence of significant linkage on chromosome 5q21 and suggestive linkage on chromosomes 8, 10, and 13. In addition, we replicated previously reported typical-migraine susceptibility loci on chromosomes 6p12.2-p21.1 and 1q21-q23, the latter being within 3 cM of the rare autosomal dominant familial hemiplegic migraine gene (ATP1A2), a finding which potentially implicates ATP1A2 in familial typical migraine for the first time. Linkage analyses of individual migraine symptoms for our six most interesting chromosomes provide tantalizing hints of the phenotypic and genetic complexity of migraine. Specifically, the chromosome 1 locus is most associated with phonophobia; the chromosome 5 peak is predominantly associated with pulsating headache; the chromosome 6 locus is associated with activity-prohibiting headache and photophobia; the chromosome 8 locus is associated with nausea/vomiting and moderate/severe headache; the chromosome 10 peak is most associated with phonophobia and photophobia; and the chromosome 13 peak is completely due to association with photophobia. These results will prove to be invaluable in the design and analysis of future linkage and linkage disequilibrium studies of migraine.     

Human homeo box-containing genes located at chromosome regions 2q31----2q37 and 12q12----12q13

Four human homeo box-containing cDNAs isolated from mRNA of an SV40-transformed human fibroblast cell line have been regionally localized on the human gene map. One cDNA clone, c10, was found to be nearly identical to the previously mapped Hox-2.1 gene at 17q21. A second cDNA clone, c1, which is 87% homologous to Hox-2.2 at the nucleotide level but is distinct from Hox-2.1 and Hox-2.2, also maps to this region of human chromosome 17 and is probably another member of the Hox-2 cluster of homeo box-containing genes. The third cDNA clone, c8, in which the homeo box is approximately 84% homologous to the mouse Hox-1.1 homeo box region on mouse chromosome 6, maps to chromosome region 12q12----12q13, a region that is involved in chromosome abnormalities in human seminomas and teratomas. The fourth cDNA clone, c13, whose homeo box is approximately 73% homologous to the Hox-2.2 homeo box sequence, is located at chromosome region 2q31----q37. The human homeo box-containing cluster of genes at chromosome region 17q21 is the human cognate of the mouse homeo box-containing gene cluster on mouse chromosome 11. Other mouse homeo box-containing genes of the Antennapedia class (class I) map to mouse chromosomes 6 (Hox-1, proximal to the IgK locus) and 15 (Hox-3). A mouse gene, En-1, with an engrailed-like homeo box (class II) and flanking region maps to mouse chromosome 1 (near the dominant hemimelia gene). Neither of the class I homeo box-containing genes--c8 and c13--maps to a region of obvious homology to chromosomal positions of the presently known mouse homeo box-containing genes.     

Assignment of the S-antigen gene (SAG) to human chromosome 2q24-q37

We report the mapping of the gene coding for the S-antigen (48-kDa protein) to human chromosome 2 using somatic cell hybrids. In situ hybridization further confirms this assignment and regionally maps the gene to 2q24-q37.     

Genetic linkage of Bietti crystallin corneoretinal dystrophy to chromosome 4q35

Bietti crystalline corneoretinal dystrophy (BCD) is an autosomal recessive retinal degeneration characterized by multiple glistening intraretinal dots scattered over the fundus, degeneration of the retina, and sclerosis of the choroidal vessels, ultimately resulting in progressive night blindness and constriction of the visual field. Although BCD has been associated with abnormalities in fatty-acid metabolism and absence of fatty-acid binding by two cytosolic proteins, the genetic basis of BCD is unknown. We report linkage of the BCD locus to D4S426 (maximum LOD score [Z(max)] 4.81; recombination fraction [straight theta] 0), D4S2688 (Zmax=3.97; straight theta=0), and D4S2299 (Zmax=5.31; straight theta=0), on chromosome 4q35-4qtel. Multipoint analysis confirmed linkage to the region telomeric of D4S1652 with a Z(max) of 5.3 located 4 cM telomeric of marker D4S2930.     

A primary linkage map of the human chromosome 11q22-23 region

We have constructed a genetic map of the human chromosomal region 11q22-23 by multipoint linkage analysis of 13 DNA polymorphisms that we have condensed into eight loci. An analysis for linkage disequilibrium between tightly linked probe/enzyme systems allows us to make specific recommendations for future DNA typing at these loci. The resulting sex-averaged multipoint map spans approximately 80 cM and differs considerably from previously reported genetic maps of this region. Our mathematically derived "most likely order" of the markers is compatible with physical mapping data using somatic cell hybrids. The known localizations of at least 14 functional genes and several disease loci to 11q22-23, including ataxia telangiectasia, make the mapping of this region especially relevant to studies of disease pathogenesis.     

A locus for brachydactyly type A-1 maps to chromosome 2q35-q36

Brachydactyly type A-1 (BDA1) was, in 1903, the first recorded example of a human anomaly with Mendelian autosomal dominant inheritance. Two large families, the affected members of which were radiographed, were recruited in the study we describe here. Two-point linkage analysis for pedigree 1 (maximum LOD score [Zmax] 6.59 at recombination fraction [theta] 0.00) and for pedigree 2 (Zmax=5.53 at straight theta=0.00) mapped the locus for BDA1 in the two families to chromosome 2q. Haplotype analysis of pedigree 1 confined the locus for family 1 within an interval of <8.1 cM flanked by markers D2S2248 and D2S360, which was mapped to chromosome 2q35-q36 on the cytogenetic map. Haplotype analysis of pedigree 2 confined the locus for family 2 within an interval of <28. 8 cM flanked by markers GATA30E06 and D2S427, which was localized to chromosome 2q35-q37. The two families had no identical haplotype within the defined region, which suggests that the two families were not related.     

Confirmation of linkage of Duane's syndrome and refinement of the disease locus to an 8.8-cM interval on chromosome 2q31

Duane's syndrome is a congenital abnormality of eye movement, which may be inherited as an autosomal dominant trait but usually occurs sporadically. Genetic mapping in a Mexican family has recently identified a locus for Duane's syndrome within a 17.8-cM region of chromosome 2q31. The region was flanked by the microsatellite markers D2S2330 and D2S364. We performed linkage and haplotype analysis in a four-generation UK family with autosomal dominant transmission of Duane's syndrome. Linkage to 2q31 was confirmed with a maximum logarithm of differences (lod) score of 3.3 at theta = 0. The genetic interval was reduced to an 8.8-cM region between markers D2S326 and D2S364 that includes the candidate homeobox D gene cluster.