Novel locus for autosomal dominant hereditary spastic paraplegia, on chromosome 8q

Hereditary spastic paraplegia (HSP) is a clinically and genetically heterogeneous group of disorders characterized by insidiously progressive spastic weakness in the legs. Genetic loci for autosomal dominant HSP exist on chromosomes 2p, 14q, and 15q. These loci are excluded in 45% of autosomal dominant HSP kindreds, indicating the presence of additional loci for autosomal dominant HSP. We analyzed a Caucasian kindred with autosomal dominant HSP and identified tight linkage between the disorder and microsatellite markers on chromosome 8q (maximum two-point LOD score 5.51 at recombination fraction 0). Our results clearly establish the existence of a locus for autosomal dominant HSP on chromosome 8q23-24. Currently this locus spans 6.2 cM between D8S1804 and D8S1774 and includes several potential candidate genes. Identifying this novel HSP locus on chromosome 8q23-24 will facilitate discovery of this HSP gene, improve genetic counseling for families with linkage to this locus, and extend our ability to correlate clinical features with different HSP loci.     

Strokes in the elderly - higher acute and 3-month mortality - an explanation

Bardet-Biedl syndrome (BBS) is a rare, autosomal recessive disease characterized by retinal dystrophy, renal structural abnormalities, obesity, dysmorphic extremities, and hypogenitalism in males. BBS is genetically heterogeneous with four known loci: BBS1 (11q), BBS2 (16q), BBS3 (3p), and BBS4 (15q). The prevalence of BBS in Newfoundland is approximately 10-fold greater than in Switzerland (1:160,000) and similar to the prevalence among the Bedouin of Kuwait (1:13,500). A population-based genetic survey was performed on 17 BBS families from the island portion of the province of Newfoundland, a comparatively isolated region of Canada. The families in the study had a total of 36 well-documented, affected individuals with 12 families having 2 or more affected individuals. Linkage at each of the four known loci was tested with two-point linkage and haplotype analysis. Three of the 17 kindreds showed linkage to 11q, 1 to 16q, and 1 to 3p. The latter is the first BBS3 family identified in a population of northern European descent. Six families remain undetermined because of poor pedigree structure or inconclusive haplotype analyses. Six families were excluded from all four known BBS loci, indicating that there is at least a fifth BBS locus (BBS5).     

Paired STSs amplified from radiation hybrids, and from associated YACs, identify highly polymorphic loci flanking the ataxia telangiectasia locus on chromosome 11q22-23

The high resolution mapping of the ataxia telangiectasia (A-T) locus on chromosome 11q22-23 requires the generation of new polymorphic markers specifically within the segment of 11q22-23 to which the locus has been assigned. We have made use of a library of Alu-PCR clones, amplified from a radiation reduced somatic cell hybrid containing the relevant chromosome 11 segment, to generate sequence tagged sites (STS) within the 11q22-23 region and have used YAC clones to extend the loci identified by these STSs. The identification of paired polymorphisms (from Alu-PCR and the associated YAC derived clone), which are physically linked, but which show minimal linkage disequilibrium, provides a highly informative haplotype for use in genetic linkage analysis in A-T families. We describe the characterisation of 2 such polymorphic loci, D11S535 and D11S611, which map between existing flanking markers, and which provide additional information on the location of the major A-T locus.     

Lupus susceptibility loci in New Zealand mice

Susceptibility to systemic lupus erythematosus has been unequivocally established to be an inherited trait, but the exact genes and how they confer susceptibility remain largely unknown. In this study of (NZB x NZW)F2 intercross mice, we used linkage analysis of markers covering > 90% of the autosomal genome and identified eight susceptibility loci (Lbw1 to -8, chromosomes 17, 4-7, 18, 1, 11, respectively) associated with antichromatin autoantibody production, glomerulonephritis, and/or mortality. Only one locus, the major histocompatibility complex, was linked to all three traits. Two other loci were associated with both glomerulonephritis and mortality, whereas the remaining loci were linked to one of the above traits. Two additional loci (Sbw1 and -2) that contributed to splenomegaly were also identified. The Sbw2 locus mapped to the identical region as Lbw2, a locus on chromosome 4 linked to glomerulonephritis and mortality, suggesting a single locus with pleiotropic effects. The results indicate that the immunopathologic features of lupus are affected by distinct, but additive, genetic contributions. Studies to determine the nature of the genes associated with these loci should help define the genetic mechanisms involved in this systemic autoimmune disease.     

Electron tomography of large, multicomponent biological structures

Genome-wide scans for linkage of chromosome regions to type 1 diabetes in affected sib pair families have revealed that the major susceptibility locus resides within the major histocompatibility complex (MHC) on chromosome 6p21 (lambda s = 2.5). It is recognised that the MHC contains multiple susceptibility loci (referred to collectively as IDDM1), including the class II antigen receptor genes, which control the major pathological feature of the disease: T lymphocyte-mediated autoimmune destruction of the insulin-producing pancreatic beta cells. However, the MHC genes, and a second locus, the insulin gene minisatellite on chromosome 11p15 (IDDM2; lambda s = 1.25), cannot account for all of the observed clustering of disease in families (lambda s = 15), and the scans suggested the presence of other susceptibility loci scattered throughout the genome. There are four additional loci for which there is currently sufficient evidence from linkage and association studies to justify fine mapping experiments: IDDM4 (FGF3/11q13), IDDM5 (ESR/6q22), IDDM8 (D6S281/6q27) and IDDM12 (CTLA-4/2q33), IDDM4, 5 and 8 were detected by genome scanning, and IDDM12 by a candidate gene strategy. The results suggest that the clustering of type 1 diabetes in families is due to the sharing of alleles at multiple loci, and that the as yet unidentified environmental factors are not causing clustering, but instead appear to influence the overall penetrance of genetically programmed susceptibility. The data are consistent with a polygenic threshold model for the inheritance of type 1 diabetes.     

Linkage analysis of candidate genes in autoimmune thyroid disease: 1. Selected immunoregulatory genes. International Consortium for the Genetics of Autoimmune Thyroid Disease

Graves' and Hashimoto's diseases are autoimmune thyroid diseases in which the genetic contribution is complex. For this reason, identification of necessary susceptibility genes has been difficult. However, a number of immunoregulatory genes have been implicated by association studies, including: CTLA-4, a recently described protein involved in antigen presentation, located on chromosome 2q33; the T-cell receptor V alpha and V beta gene complexes, located on 14q11 and 7q35, respectively; and the Ig gene complex (IgH), located on 15q11. We used polymorphic microsatellite markers located within these genes, or gene complexes, to test for linkage (rather than association), to each of these candidates. Using markers within the loci allowed us to assume a fixed recombination fraction of 0.01 in the tested model. Three hundred eight subjects from 48 multiplex families were studied, with 142 affected subjects. Using this set of families, we have previously shown evidence of linkage with a major susceptibility locus for Graves' disease (GD-1) on 14q24.3-31, with a maximum lod (logarithm + odds) score of 2.1, at a penetrance of 80% and with a dominant mode of inheritance. In the present study, we obtained consistently negative lod scores for each of the candidate genes, assuming either dominant or recessive modes of inheritance. These data, therefore, showed evidence against linkage with all the candidate genes. Unlike association studies, linkage analyses detect major genetic influences on disease susceptibility exerted by the linked loci. The lack of linkage for the immunoregulatory genes that were studied indicated, therefore, that they were not major contributors to disease etiology.     

A new locus for hemiplegic migraine maps to chromosome 1q31

A single familial hemiplegic migraine locus has been previously mapped to 19p13.1 and associated with mutations in a calcium channel gene (CACNL1A4). We describe a new 39-member four-generation family from Wyoming of German-Native American descent with autosomal dominant familial hemiplegic migraine that is not linked to the chromosome 19p locus. Affected individuals showed a stereotypic pattern of migrainous headache associated with hemisensory and hemiparetic attacks, without other headache types. Eighty-three percent reported minor head trauma as a trigger for individual attacks. Seventy-two percent reported other typical migraine triggers for the attacks. Attack frequency decreased with age and the overall course was benign. Genetic linkage studies of this family found strong evidence for the disease gene in this family being located at chromosome 1q31. Multipoint analysis showed lod scores > 3 in a 44-cm region flanked by D1S158 and D1S2781, using 80% penetrance and a phenocopy rate of 1/50. Haplotype and multipoint analysis, including flanking markers, suggested incomplete penetrance and variable expressivity of the disease. A single affected patient who reports atypical symptoms including daily headaches likely represents a phenocopy. This new locus for hemiplegic migraine suggests that mutations of additional calcium channels in the region may cause the disease.     

A disease locus for familial hypertrophic cardiomyopathy maps to chromosome 1q3

Familial hypertrophic cardiomyopathy (FHC) is caused by missense mutations in the beta cardiac myosin heavy chain (MHC) gene in less than half of affected individuals. To identify the location of another gene involved in this disorder, a large family with FHC not linked to the beta MHC gene was studied. Linkage was detected between the disease in this family and a locus on chromosome 1q3 (maximum multipoint lod score = 8.47). Analyses in other families with FHC not linked to the beta MHC gene, revealed linkage to the chromosome 1 locus in two and excluded linkage in six. Thus mutations in at least three genetic loci can cause FHC. Three sarcomeric contractile proteins--troponin I, tropomyosin and actin--are strong candidate FHC genes at the chromosome 1 locus.     

Linkage studies in dominant optic atrophy, Kjer type: possible evidence for heterogeneity

Dominant optic atrophy, Kjer type, is an autosomal dominant disorder causing progressive loss of visual acuity and colour vision from early childhood. The gene (OPA1) has variable expressivity, a penetrance of 0.98, and the locus has been localised to 3q28-29. We have genotyped nine British families with the disease using 12 polymorphic microsatellite markers from this region. Linkage and haplotype analysis shows the OPA1 gene to be located in a 2.3 cM interval between markers D3S1601 and D3S2748. One family showed no evidence of linkage with the chromosome 3 markers, suggesting for the first time that locus heterogeneity for this disease may exist, although exclusion for linkage is based on unaffected subjects. In addition, analysis of recombinants has enabled us to order the 12 markers along chromosome 3.     

Identification of novel susceptibility loci for inflammatory bowel disease on chromosomes 1p, 3q, and 4q: evidence for epistasis between 1p and IBD1

The idiopathic inflammatory bowel diseases, Crohn's disease (CD) and ulcerative colitis (UC), are chronic, frequently disabling diseases of the intestines. Segregation analyses, twin concordance, and ethnic differences in familial risks have established that CD and UC are complex, non-Mendelian, related genetic disorders. We performed a genome-wide screen using 377 autosomal markers, on 297 CD, UC, or mixed relative pairs from 174 families, 37% Ashkenazim. We observed evidence for linkage at 3q for all families (multipoint logarithm of the odds score (MLod) = 2.29, P = 5.7 x 10(-4)), with greatest significance for non-Ashkenazim Caucasians (MLod = 3.39, P = 3.92 x 10(-5)), and at chromosome 1p (MLod = 2.65, P = 2.4 x 10(-4)) for all families. In a limited subset of mixed families (containing one member with CD and another with UC), evidence for linkage was observed on chromosome 4q (MLod = 2.76, P = 1.9 x 10(-4)), especially among Ashkenazim. There was confirmatory evidence for a CD locus, overlapping IBD1, in the pericentromeric region of chromosome 16 (MLod = 1.69, P = 2.6 x 10(-3)), particularly among Ashkenazim (MLod = 1.51, P = 7.8 x 10(-3)); however, positive MLod scores were observed over a very broad region of chromosome 16. Furthermore, evidence for epistasis between IBD1 and chromosome 1p was observed. Thirteen additional loci demonstrated nominal (MLod > 1.0, P < 0.016) evidence for linkage. This screen provides strong evidence that there are several major susceptibility loci contributing to the genetic risk for CD and UC.     

Autosomal dominant medullary cystic kidney disease: evidence of gene locus heterogeneity

Autosomal dominant medullary cystic kidney disease (ADMCKD; synonym: medullary cystic disease, MCD) is an autosomal dominant kidney disorder, sharing morphological and clinical features with recessive juvenile nephronophthisis (NPH), such as reduced urinary concentration ability and multiple renal cysts at the corticomedullary junction. While in NPH end-stage renal disease (ESRD) occurs in adolescence, ADMCKD leads to ESRD in adulthood. Recently a gene locus for ADMCKD has been localized to chromosome 1q21 in two large Cypriot families. This prompted us to examine linkage in three ADMCKD-families, using the same set of polymorphic microsatellite markers spanning the critical region on chromosome 1q21. Haplotype analysis revealed that none of the three families showed linkage to this locus, thus demonstrating evidence for genetic locus heterogeneity. Additional linkage analysis studies need to be performed in order to identify further gene loci cosegregating with this autosomal dominant kidney disorder.     

Assessment of the interphotoreceptor matrix proteoglycan-1 (IMPG1) gene localised to 6q13-q15 in autosomal dominant Stargardt-like disease (ADSTGD), progressive bifocal chorioretinal atrophy (PBCRA), and North Carolina macular dystrophy (MCDR1)

We have recently characterised the genomic organisation of a novel interphotoreceptor matrix proteoglycan, IMPG1, and have mapped the gene locus to chromosome 6q13-q15 by fluorescence in situ hybridisation. As the interphotoreceptor matrix (IPM) is thought to play a critical role in retinal adhesion and the maintenance of photoreceptor cells, it is conceivable that a defect in one of the IPM components may cause degenerative lesions in retinal structures and thus may be associated with human retinopathies. By genetic linkage analysis, several retinal dystrophies including one form of autosomal dominant Stargardt-like macular dystrophy (STGD3), progressive bifocal chorioretinal atrophy (PBCRA), and North Carolina macular dystrophy (MCDR1) have previously been localised to a region on proximal 6q that overlaps the IMPG1 locus. We have therefore assessed the entire coding region of IMPG1 by exon amplification and subsequent single stranded conformational analysis in patients from 6q linked multigeneration families diagnosed with PBCRA and MCDR1, as well as a single patient from an autosomal dominant STGD pedigree unlinked to either of the two known STGD2 and STGD3 loci on chromosomes 13q and 6q, respectively. No disease associated mutations were identified. In addition, using an intragenic polymorphism, IMPG1 was excluded by genetic recombination from both the PBCRA and the MCDR1 loci. However, as the autosomal dominant Stargardt-like macular dystrophies are genetically heterogeneous, other forms of this disorder, in particular STGD3 previously linked to 6q, may be caused by mutations in IMPG1.     

Affected-sib-pair mapping of a novel susceptibility gene to insulin-dependent diabetes mellitus (IDDM8) on chromosome 6q25-q27

Affected-sib-pair analyses were performed using 104 Caucasian families to map genes that predispose to insulin-dependent diabetes mellitus (IDDM). We have obtained linkage evidence for D6S446 (maximum lod score [MLS] = 2.8) and for D6S264 (MLS = 2.0) on 6q25-q27. Together with a previously reported data set, linkage can be firmly established (MLS = 3.4 for D6S264), and the disease locus has been designated IDDM8. With analysis of independent families, we confirmed linkage evidence for the previously identified IDDM3 (15q) and DDM7 (2q). We also typed additional markers in the regions containing IDDM3, IDDM4, IDDM5, and IDDM8. Preliminary linkage evidence for a novel region on chromosome 4q (D4S1566) has been found in 47 Florida families (P < .03). We also found evidence of linkage for two regions previously identified as potential linkages in the Florida subset: D3S1303 on 3q (P < .04) and D7S486 on 7q (P < .03). We could not confirm linkage with eight other regions (D1S191, D1S412, D4S1604, D8S264, D8S556, D10S193, D13S158, and D18S64) previously identified as potential linkages.     

Hereditary lymphedema: evidence for linkage and genetic heterogeneity

Hereditary or primary lymphedema is a developmental disorder of the lymphatic system which leads to a disabling and disfiguring swelling of the extremities. Hereditary lymphedema generally shows an autosomal dominant pattern of inheritance with reduced penetrance, variable expression and variable age at onset. Three multigeneration families demonstrating the phenotype of hereditary lymphedema segregating as an autosomal dominant trait with incomplete penetrance were genotyped for 366 autosomal markers. Linkage analysis yielded a two-point LOD score of 6.1 at straight theta = 0. 0 for marker D5S1354 and a maximum multipoint LOD score of 8.8 at marker D5S1354 located at chromosome 5q34-q35. Linkage analysis in two additional families using markers from the linked region showed one family consistent for linkage to distal chromosome 5. In the second family, linkage to 5q was excluded for all markers in the region with LOD scores Z < -2.0. The vascular endothelial growth factor C receptor ( FLT4 ) was mapped to the linked region, and partial sequence analysis identified a G-->A transition at nucleotide position 3360 of the FLT4 cDNA, predicting a leucine for proline substitution at residue 1126 of the mature receptor in one nuclear family. This study localizes a gene for primary lymphedema to distal chromosome 5q, identifies a plausible candidate gene in the linked region, and provides evidence for a second, unlinked locus for primary lymphedema.     

In vitro evaluation of potential drug interactions with levetiracetam, a new antiepileptic agent

Cerebral cavernomas (CCMs) are vascular malformations that may be inherited as an autosomal dominant condition for which a gene, CCM1, was mapped to chromosome 7. Poorly defined cutaneous malformations were sometimes described in association with CCMs. During a national survey, 57 French CCM families were studied. Co-occurrence of CCMs and a distinctive cutaneous vascular malformation was observed in 4 families. Ten individuals belonging to these families showed similar hyperkeratotic cutaneous capillary venous malformations (HCCVMs). In 3 families, the histology showed orthokeratosis and hyperkeratosis as well as dilated capillaries in the dermis extending to the hypodermis and confirmed the diagnosis of HCCVM. Genetic analysis strongly supports linkage of these families to the CCM1 locus on chromosome 7. The HCCVM seems to be a peculiar cutaneous vascular malformation associated with CCMs. These data strongly suggest that HCCVMs and CCMs in these families are due to the same genetic abnormality.     

Peutz-Jeghers syndrome: confirmation of linkage to chromosome 19p13.3 and identification of a potential second locus, on 19q13.4

Peutz-Jeghers syndrome (PJS) is an autosomal dominant disease with variable expression and incomplete penetrance, characterized by mucocutaneous pigmentation and hamartomatous polyposis. Patients with PJS have increased frequency of gastrointestinal and extraintestinal malignancies (ovaries, testes, and breast). In order to map the locus (or loci) associated with PJS, we performed a genomewide linkage analysis, using DNA polymorphisms in six families (two from Spain, two from India, one from the United States, and one from Portugal) comprising a total of 93 individuals, including 39 affected and 48 unaffected individuals and 6 individuals with unknown status. During this study, localization of a PJS gene to 19p13.3 (around marker D19S886) had been reported elsewhere. For our families, marker D19S886 yielded a maximum LOD score of 4.74 at a recombination fraction (theta) of .045; multipoint linkage analysis resulted in a LOD score of 7.51 for the interval between D19S886 and 19 pter. However, markers on 19q13.4 also showed significant evidence for linkage. For example, D19S880 resulted in a maximum LOD score of 3.8 at theta = .13. Most of this positive linkage was contributed by a single family, PJS07. These results confirm the mapping of a common PJS locus on 19p13.3 but also suggest the existence, in a minority of families, of a potential second PJS locus, on 19q13.4. Positional cloning and characterization of the PJS mutations will clarify the genetics of the syndrome and the implication of the gene(s) in the predisposition to neoplasias.     

The genetics of psoriasis: a complex disorder of the skin and immune system

In the last few years, molecular genetics analyses have permitted novel insights into psoriasis, a disease characterized by uncontrolled proliferation of keratinocytes and recruitment of T cells into the skin. The disease affects approximately 1-2% of the Caucasian population and can occur in association with other inflammatory diseases such as Crohn's disease and in association with human immunodeficiency virus (HIV) infection. Given that psoriasis has characteristics of an autoimmune disease, it is not surprising that HLA studies revealed an association with certain alleles, notably HLA-Cw6. Despite this HLA component, psoriasis in some families is inherited as an autosomal dominant trait with high penetrance. Loci at chromosome 17q25 and 4q have been identified following genome-wide linkage scans of large, multiply affected families. In the case of at least the susceptibility locus at 17q25, the development of psoriasis does not require the presence of HLA-Cw6. Sib-pair analyses have confirmed the association with HLA-Cw6, confirmed the existence of a locus at 17q25 and identified other possible susceptibility loci. Two independent groups have reported a third region on chromosome 20p. Despite these findings, the extent of genetic heterogeneity and the role of environmental triggers and modifier genes is still not clear. The precise role of HLA also still needs to be defined. The isolation of novel susceptibility genes will provide insights into the precise biochemical pathways that control this disease. Such pathways will also reveal additional candidate genes that can be tested for molecular alterations resulting in disease susceptibility.     

Childhood absence epilepsy with tonic-clonic seizures and electroencephalogram 3-4-Hz spike and multispike-slow wave complexes: linkage to chromosome 8q24

Childhood absence epilepsy (CAE), a common form of idiopathic generalized epilepsy, accounts for 5%-15% of childhood epilepsies. To map the chromosomal locus of persisting CAE, we studied the clinical and electroencephalographic traits of 78 members of a five-generation family from Bombay, India. The model-free affected-pedigree member method was used during initial screening with chromosome 6p, 8q, and 1p microsatellites, and only individuals with absence seizures and/or electroencephalogram 3-4-Hz spike- and multispike-slow wave complexes were considered to be affected. Significant P values of .00000-.02 for several markers on 8q were obtained. Two-point linkage analysis, assuming autosomal dominant inheritance with 50% penetrance, yielded a maximum LOD score (Zmax) of 3.6 for D8S502. No other locus in the genome achieved a significant Zmax. For five smaller multiplex families, summed Zmax was 2.4 for D8S537 and 1.7 for D8S1761. Haplotypes composed of the same 8q24 microsatellites segregated with affected members of the large family from India and with all five smaller families. Recombinations positioned the CAE gene in a 3.2-cM interval.     

Evidence that a gene for essential tremor maps to chromosome 2p in four families

In this Journal, we previously reported genetic linkage between loci on chromosome (chr)2p(ETM) and dominantly inherited essential tremor (ET) in a large American kindred of Czech ancestry. Other investigators reported another ET susceptibility locus on chr 3q (FET1) which accounted for over half of the Icelandic families that were studied. We now report evidence for linkage to the ETM locus in three additional, unrelated American families with ET and exclude the FET1 locus in these families. Fine mapping results, using an "affecteds-only" model in all four American families, demonstrate positive combined pairwise lod scores (Z) at the ETM locus with aZ(max) = 5.94 at a recombination fraction (theta) = 0.00 for locus D2S220. Haplotype reconstruction places the ETM gene in a 9.10 cM interval between the D2S224 and D2S405 loci. Multipoint linkage analysis suggests that the ETM gene is in the 2.18 cM interval between loci D2S2150 and D2S220 with a Z(max) = 8.12. These findings may facilitate the search for a gene that causes ET and may further our understanding of other disorders that are associated with tremor [corrected].     

Identification of a hereditary pancreatitis mutation in four West Virginia families

Hereditary pancreatitis (HP) is the second most common cause of chronic childhood pancreatitis in the United States. Mutations in the cationic trypsinogen gene on chromosome 7 are known to cause HP. We identified four families in West Virginia with symptoms consistent with HP. To determine whether members of these families had defects in the trypsinogen gene, we tested for linkage between the HP gene and simple tandem repeat markers on chromosome 7q and screened for a specific mutation in the cationic trypsinogen gene. Two-point linkage analysis indicated that the disease gene is closely linked to three 7q markers (D7S661, D7S2511, and D7S1805). Restriction fragment length polymorphism analysis showed that all clinically affected members and nonpenetrant carriers from the four families carried a G to A mutation in the third exon of the trypsinogen gene. These findings indicate that this mutation is the cause of HP in the families in our study. The observation that most individuals who carry the mutation have symptoms of HP is consistent with the high but incomplete penetrance of the trait. The presence of a single mutation and a common linked haplotype indicates that the defective allele arose in an ancestor common to all four families.