A major locus for myoclonus-dystonia maps to chromosome 7q in eight families

Myoclonus-dystonia (M-D) is an autosomal dominant disorder characterized by myoclonic and dystonic muscle contractions that are often responsive to alcohol. The dopamine D2 receptor gene (DRD2) on chromosome 11q has been implicated in one family with this syndrome, and linkage to a 28-cM region on 7q has been reported in another. We performed genetic studies, using eight additional families with M-D, to assess these two loci. No evidence for linkage was found for 11q markers. However, all eight of these families showed linkage to chromosome 7 markers, with a combined multipoint LOD score of 11.71. Recombination events in the families define the disease gene within a 14-cM interval flanked by D7S2212 and D7S821. These data provide evidence for a major locus for M-D on chromosome 7q21.     

Evidence for locus heterogeneity in acrocephalosyndactyly: a refined localization for the Saethre-Chotzen syndrome locus on distal chromosome 7p--and exclusion of Jackson-Weiss syndrome from craniosynostosis loci on 7p and 5q.

Craniosynostosis (premature fusion of the skull sutures) occurs as a clinically heterogeneous group of disorders, frequently involving digital abnormalities. We have previously provisionally assigned the gene for one such condition, Saethre-Chotzen syndrome (ACS III), to chromosome 7p. Linkage analysis is now reported between ACS III and dinucleotide repeat loci on distal 7p. The maximum lod scores, Zmax, were 5.57 at a recombination fraction of .05, with D7S488, and 4.74 at a recombination fraction of .05, with D7S493. Only weak linkage, not reaching significance, was found with distal markers (D7S513 and afm281vc9) and a proximal marker (D7S516). Multipoint analysis shows that the disease locus lies between D7S513 and D7S516. Analysis of individual recombinants shows that the most likely position is between D7S493 and D7S516. Linkage data in regard of Jackson-Weiss syndrome demonstrate that this autosomal dominant form of acrocephalosyndactyly does not map to the ACS III region on 7p or to the acrocephalosyndactyly locus on 5q (Boston type). These findings underline the genetic heterogeneity among the different clinical conditions manifesting with acrocephalosyndactyly.     

Genetic linkage to chromosome 22q12 for a heavy-smoking quantitative trait in two independent samples

We conducted a genomewide linkage screen of a simple heavy-smoking quantitative trait, the maximum number of cigarettes smoked in a 24-h period, using two independent samples: 289 Australian and 155 Finnish nuclear multiplex families, all of which were of European ancestry and were targeted for DNA analysis by use of probands with a heavy-smoking phenotype. We analyzed the trait, using a regression of identity-by-descent allele sharing on the sum and difference of the trait values for relative pairs. Suggestive linkage was detected on chromosome 22 at 27-29 cM in each sample, with a LOD score of 5.98 at 26.96 cM in the combined sample. After additional markers were used to localize the signal, the LOD score was 5.21 at 25.46 cM. To assess the statistical significance of the LOD score in the combined sample, 1,000 simulated genomewide screens were conducted, resulting in an empirical P value of .006 for the LOD score of 5.21. This linkage signal is driven mainly by the microsatellite marker D22S315 (22.59 cM), which had a single-point LOD score of 5.41 in the combined sample and an empirical P value <.001 from 1,000 simulated genomewide screens. This marker is located within an intron of the gene ADRBK2, encoding the beta-adrenergic receptor kinase 2. Fine mapping of this linkage region may reveal variants contributing to heaviness of smoking, which will lead to a better understanding of the genetic mechanisms underlying nicotine dependence.     

A genomewide screen for autism-spectrum disorders: evidence for a major susceptibility locus on chromosome 3q25-27

To identify genetic loci for autism-spectrum disorders, we have performed a two-stage genomewide scan in 38 Finnish families. The detailed clinical examination of all family members revealed infantile autism, but also Asperger syndrome (AS) and developmental dysphasia, in the same set of families. The most significant evidence for linkage was found on chromosome 3q25-27, with a maximum two-point LOD score of 4.31 (Z(max )(dom)) for D3S3037, using infantile autism and AS as an affection status. Six markers flanking over a 5-cM region on 3q gave Z(max dom) >3, and a maximum parametric multipoint LOD score (MLS) of 4.81 was obtained in the vicinity of D3S3715 and D3S3037. Association, linkage disequilibrium, and haplotype analyses provided some evidence for shared ancestor alleles on this chromosomal region among affected individuals, especially in the regional subisolate. Additional potential susceptibility loci with two-point LOD scores >2 were observed on chromosomes 1q21-22 and 7q. The region on 1q21-22 overlaps with the previously reported candidate region for infantile autism and schizophrenia, whereas the region on chromosome 7q provided evidence for linkage 58 cM distally from the previously described autism susceptibility locus (AUTS1).     

Sperm chromosome analysis in a man heterozygous for a paracentric inversion of chromosome 7 (q11q22)

Summary Human sperm chromosomes were studied in a man heterozygous for a paracentric inversion of chromosome 7 (q11q22). The pronuclear chromosomes were analysed after in vitro penetration of golden hamster (Mesocricetus auratus) eggs. Ninety-four sperm chromosome spreads were examined, of which 34 contained the normal number 7 chromosome and 59 the inverted 6. This segregation was significantly different from the expected 1:1 ratio. The number of X- to Y-bearing sperm was 48 and 46 respectively. No sperm contained a recombinant chromosome caused by a crossover within the inversion. The frequency of chromosomal abnormalities in other chromosomes was 9.6%, which is not significantly different from the frequency observed in normal donors (8.9%) in our laboratory. These result suggest that the risk of chromosomally unbalanced sperm is not high for this paracentric inversion.     

Genetic heterogeneity in benign familial neonatal convulsions: identification of a new locus on chromosome 8q.

The syndrome of benign familial neonatal convulsions (BFNC) is a rare autosomal dominant disorder characterized by unprovoked seizures in the first few weeks of life. One locus for BFNC has been mapped to chromosome 20 in several pedigrees, but we have excluded linkage to chromosome 20 in one large kindred. In order to identify this novel BFNC locus, dinucleotide repeat markers distributed throughout the genome were used to screen this family. Maximum pairwise LOD scores of 4.43 were obtained with markers D8S284 and D8S256 on chromosome 8q. Multipoint analysis placed the BFNC locus in the interval spanned by D8S198-D8S274. This study establishes the presence of a new BFNC locus and confirms genetic heterogeneity of this disorder.     

Identification of a new locus for medullary cystic disease, on chromosome 16p12.

Autosomal dominant medullary cystic disease (ADMCKD) is an interstitial nephropathy that has morphologic and clinical features similar to autosomal recessive nephronophthisis. The typical renal dysfunction associated with ADMCKD results mainly from a defect in urinary concentration ability, although results of urinalysis are normal. Recently, a locus on chromosome 1 was associated with ADMCKD, in DNA from two large Cypriot families, and genetic heterogeneity was inferred. We describe the genomewide linkage mapping of a new locus for medullary cystic disease, ADMCKD2, on chromosome 16p12 in a four-generation Italian pedigree. The family with ADMCKD2 fulfills the typical diagnostic criteria of ADMCKD, complicated by hyperuricemia and gouty arthritis. Marker D16S3036 shows a maximum two-point LOD score of 3.68, and the defined critical region spans 10.5 cM, between D16S500 and SCNN1B1-2. Candidate genes included in the critical region are discussed.     

A major susceptibility locus on chromosome 22q12 plays a critical role in the control of kala-azar

Kala-azar (KA) is a life-threatening protozoal disease caused by Leishmania parasites (L. donovani, L. chagasi, and L. infantum). The disease, which is also called "visceral leishmaniasis," is prevalent in Africa, South America, Asia, and the Mediterranean basin. Epidemics occur periodically, killing a large number of infected individuals. Factors determining whether a patient remains asymptomatic or develops KA are still largely unknown. In a previous study that was performed during an outbreak of KA in a village on the Ethiopian-Sudanese border, we showed that KA was more frequent in certain families and ethnic groups, thereby suggesting that host genetic factors play an important role in the development of the disease. Here, we report the results of a genomewide linkage study performed on 63 Sudanese families selected from the most affected ethnic group and including 169 children with KA. Significant linkage (LOD score 3.50 [P=3x10-5] in all patients; LOD score 3.90 [P=10-5] in patients who were affected early in the outbreak) was obtained with markers on chromosome 22q12. These results are the first evidence of a major genetic effect on the development of human KA. They may lead to identification of genes critical in the pathogenesis of this disease and to new therapeutic interventions against this parasite, which is developing resistance to available drugs.     

Haplotype mapping of a major quantitative-trait locus for fetal hemoglobin production, on chromosome 6q23.

Fetal hemoglobin (Hb F) and fetal cell (FC) levels in adults show considerable variation and are influenced by several genetic variants; the major determinants appear to be unlinked to the beta-globin gene cluster. Recently, a trans-acting locus controlling Hb F and FC production has been mapped to chromosome 6q23 in an Asian Indian kindred that includes individuals with heterocellular hereditary persistence of Hb F (HPFH) associated with beta thalassemia. We have extended the kindred by 57 members, bringing the total studied to 210, and have saturated the region with 26 additional markers. Linkage analysis showed tight linkage of the quantitative-trait locus (QTL) to the anonymous markers D6S976 (LOD score 11.3; recombination fraction .00) and D6S270 (LOD score 7.4; recombination fraction .00). Key recombination events now place this QTL within a 1-2-cM interval spanning approximately 1.5 Mb between D6S270 and D6S1626. Furthermore, haplotype analysis has led to a reevaluation of the genealogy and to the identification of additional relationships in the kindred.     

Owl monkey gene map: evidence for a homologous human chromosome 7q region near the cystic fibrosis locus

We have demonstrated the assignments of two gene loci (COLIA2, MET) and two noncoding DNA markers (D7S13, D7S8) to owl monkey chromosome 14 (K-VI) by hybridizing DNA probes from the cystic fibrosis (CF) region of human chromosome 7q21-32 to panels of rodent-owl monkey somatic cell hybrids. The assignments are substantiated by in situ chromosome hybridization of markers COLIA2, MET, and D7S13 to the distal long arm of chromosome 14 (K-VI). These results support genomic conservation of the human CF region, at least in the higher primates.     

Segregation analysis in a man heterozygous for a pericentric inversion of chromosome 7 (p13;q36) by sperm chromosome studies.

We have analyzed 140 sperm chromosome complements from a subfertile man heterozygous for an inv(7)(p13;q36). Seventy-five percent of the chromosome complements were not recombinant: 37.9% contained the normal chromosome 7, and 37.1% contained the inverted chromosome 7. Twenty-five percent of the 140 were recombinant: 7.1% carried a recombinant chromosome 7 with a duplication p and deletion q, 17.1% carried a recombinant chromosome 7 with a duplication q and deletion p, and 0.7% carried both recombinant chromosomes. The frequency of structural chromosomal aberrations unrelated to the inversion was 11.4%, and the frequency of aneuploidy was 2.9%. Both frequencies were not significantly different from those in control donors. Two sperm complements with a second independent, contiguous inversion involving one of the original breakpoints (q36) were observed (1.4%). The risk of producing chromosomally abnormal offspring or spontaneous abortions would be 34.3%. The proportion of X-bearing and Y-bearing sperm was 46.8% and 53.2%, respectively, not significantly different from the expected 1:1 ratio.     

Multipoint genome-wide linkage scan for nonword repetition in a multigenerational family further supports chromosome 13q as a locus for verbal trait disorders

Verbal trait disorders encompass a wide range of conditions and are marked by deficits in five domains that impair a person’s ability to communicate: speech, language, reading, spelling, and writing. Nonword repetition is a robust endophenotype for verbal trait disorders that is sensitive to cognitive processes critical to verbal development, including auditory processing, phonological working memory, and motor planning and programming. In the present study, we present a six-generation extended pedigree with a history of verbal trait disorders. Using genome-wide multipoint variance component linkage analysis of nonword repetition, we identified a region spanning chromosome 13q14–q21 with LOD = 4.45 between 52 and 55 cM, spanning approximately 5.5 Mb on chromosome 13. This region overlaps with SLI3, a locus implicated in reading disability in families with a history of specific language impairment. Our study of a large multigenerational family with verbal trait disorders further implicates the SLI3 region in verbal trait disorders. Future studies will further refine the specific causal genetic factors in this locus on chromosome 13q that contribute to language traits.     

The size of the plasmacytoid dendritic cell compartment is a multigenic trait dominated by a locus on mouse chromosome 7

Plasmacytoid dendritic cells (pDC) compose one of the many distinct dendritic cell subsets. The primary function of pDC is to potently produce type 1 IFNs upon stimulation, which is highly relevant in antiviral responses. Consequently, the ability to manipulate the size of the pDC compartment in vivo may increase the capacity to clear viral infections. In an attempt to identify genetic loci affecting the size of the pDC compartment, defined by both the proportion and absolute number of pDC, we undertook an unbiased genetic approach. Linkage analysis using inbred mouse strains identified a locus on chromosome 7 (Pdcc1) significantly linked to both the proportion and the absolute number of pDC in the spleen. Moreover, loci on either chromosome 11 (Pdcc2) or 9 (Pdcc3) modified the effect of Pdcc1 on chromosome 7 for the proportion and absolute number of pDC, respectively. Further analysis using mice congenic for chromosome 7 confirmed Pdcc1, demonstrating that variation within this genetic interval can regulate the size of the pDC compartment. Finally, mixed bone marrow chimera experiments showed that both the proportion and the absolute number of pDC are regulated by cell-intrinsic hematopoietic factors. Our findings highlight the multigenic regulation of the size of the pDC compartment and will facilitate the identification of genes linked to this trait.     

Genetic aberration in primary hepatocellular carcinoma：correlation between p53 gene mutation and loss—of—heterozygosity on chromosome 16q21—q23 and 9p21—p23

To elucidate the molecular pathology underlying the development of hepatocellular carcinoma (HCC),we used 41 highly polymorphic microsatellite markers to examine 55 HCC and corresponding non-tumor liver tissues on chromosome 9,16 and 17.Loss-of-heterozygosity(LOH) is observed with high frequency on chromosomal region 17p13(36k/55,65%),9q21-p23(28/55,51%),16q21-23(27/55,49%) in tumors.Meanwhile,microsatellite instability is rarely found in these microsatellite loci.Direct sequencing was performed to detect the tentative mutation of tumor wuppressor genes in these regions:p53,MTS1/p16,and CDH1/E-cadherin.Wihin exon 5-9 of p53 gene,14 out of 55 HCC specimens(24%) have somatic mutations,and nucleotide deletion of this gene is reported in HCC for the first time.Mutation in MTS1/p16 is found only in one tumor case.We do not find mutations in CDH1/E-cadherin.Furthermore,a statistically significant correlation is present between p53 gene mutation and loss of chromosome region 16q21-q23 and 9p21-p23,which indicates that synergism between p53 inactivation and deletion of 16q21-q23 and 9p21-p23 may play a role in the pathogenesis of HCC.     

Genetic and physical mapping of the locus for autosomal dominant renal Fanconi syndrome, on chromosome 15q15.3

Autosomal dominant renal Fanconi syndrome is a genetic model for the study of proximal renal tubular transport pathology. We were able to map the locus for this disease to human chromosome 15q15.3 by genotyping a central Wisconsin pedigree with 10 affected individuals. After a whole-genome scan with highly polymorphic simple sequence repeat markers, a maximum LOD score of 3.01 was calculated for marker D15S659 on chromosome 15q15.3. Linkage and haplotype analysis for an additional 24 markers flanking D15S659 narrowed the interval to approximately 3 cM, with the two highest single-point LOD scores observed being 4.44 and 4.68 (for D15S182 and D15S537, respectively). Subsequently, a complete bacterial artificial chromosome contig was constructed, from the High Throughput Genomic Sequence Database, for the region bounded by D15S182 and D15S143. The identification of the gene and gene product altered in autosomal dominant renal Fanconi syndrome will allow the study of the physiology of proximal renal tubular transport.