Resolution of the two loci for autosomal dominant aniridia, AN1 and AN2, to a single locus on chromosome 11p13.

Two distinct loci have been proposed for aniridia; AN1 for autosomal dominant aniridia on chromosome 2p and AN2 for the aniridia in the WAGR contiguous gene syndrome on chromosome 11p13. In this report, the kindred segregating for autosomal dominant aniridia, which suggested linkage to acid phosphatase-1 (ACP1) and led to the assignment of the AN1 locus on chromosome 2p, has been updated and expanded. Linkage analysis between the aniridia phenotype and ACP1 does not support the original linkage results, excluding linkage up to theta = 0.17 with Z = -2. Tests for linkage to other chromosome 2p markers. APOB, D2S71, D2S5, and D2S1, also excluded linkage to aniridia. Markers that have been isolated from the chromosome 11p13 region were then analyzed in this aniridia family. Two RFLPs at the D11S323 locus give significant evidence for linkage. The PvuII polymorphism detected by probe p5S1.6 detects no recombinants, with a maximum lod score of Z = 6.97 at theta = 0.00. The HaeIII polymorphism detected by the probe p5BE1.2 gives a maximum lod score of Z = 2.57 at theta = 0.00. Locus D11S325 gives a lod score of Z = 1.53 at theta = 0.00. These data suggest that a locus for aniridia (AN1) on chromosome 2p has been misassigned and that this autosomal dominant aniridia family is segregating for an aniridia mutation linked to markers in the 11p13 region.     

Genetic heterogeneity in X-linked amelogenesis imperfecta.

The AMELX gene located at Xp22.1-p22.3 encodes for the enamel protein amelogenin and has been implicated as the gene responsible for the inherited dental abnormality X-linked amelogenesis imperfecta (XAI). Three families with XAI have been investigated using polymorphic DNA markers flanking the position of AMELX. Using two-point linkage analysis, linkage was established between XAI and several of these markers in two families, with a combined lod score of 6.05 for DXS16 at theta = 0.04. This supports the involvement of AMELX, located close to DXS16, in the XAI disease process (AIH1) in those families. Using multipoint linkage analysis, the combined maximum lod score for these two families was 7.30 for a location of AIH1 at 2 cM distal to DXS16. The support interval around this location extended about 8 cM proximal to DXS92, and the AIH1 location could not be precisely defined by multipoint mapping. Study of recombination events indicated that AIH1 lies in the interval between DXS143 and DXS85. There was significant evidence against linkage to this region in the third family, indicating locus heterogeneity in XAI. Further analysis with markers on the long arm of the X chromosome showed evidence of linkage to DXS144E and F9 with no recombination with either of these markers. Two-point analysis gave a peak lod score at DXS144E with a maximum lod score of 2.83 at theta = 0, with a peak lod score in multipoint linkage analysis of 2.84 at theta = 0. The support interval extended 9 cM proximal to DXS144E and 14 cM distal to F9.(ABSTRACT TRUNCATED AT 250 WORDS)     

A high-density genetic linkage map of a black spruce (Picea mariana) × red spruce (Picea rubens) interspecific hybrid

Genetic maps provide an important genomic resource of basic and applied significance. Spruce (Picea) has a very large genome size (between 0.85 × 1010 and 2.4 × 1010 bp; 8.5-24.0 pg/1C, a mean of 17.7 pg/1C ). We have constructed a near-saturated genetic linkage map for an interspecific backcross (BC1) hybrid of black spruce (BS; Picea mariana (Mill.) B.S.P.) and red spruce (RS; Picea rubens Sarg.), using selectively amplified microsatellite polymorphic loci (SAMPL) markers. A total of 2284 SAMPL markers were resolved using 31 SAMPL-MseI selective nucleotide primer combinations. Of these, 1216 SAMPL markers showing Mendelian segregation were mapped, whereas 1068 (46.8%) SAMPL fragments showed segregation distortion at α = 0.05. Maternal, paternal, and consensus maps consistently coalesced into 12 linkage groups, corresponding to the haploid chromosome number (1n = 1x = 12) of 12 in the genus Picea. The maternal BS map consisted of 814 markers distributed over 12 linkage groups, covering 1670 cM, with a mean map distance of 2.1 cM between adjacent markers. The paternal BS × RS map consisted of 773 markers distributed over 12 linkage groups, covering 1563 cM, with a mean map distance of 2.0 cM between adjacent markers. The consensus interspecific hybrid BC1 map consisted of 1216 markers distributed over 12 linkage groups, covering 1865 cM (98% genome coverage), with a mean map distance of 1.5 cM between adjacent markers. The genetic map reported here provides an important genomic resource in Picea, Pinaceae, and conifers.     

A microsatellite polymorphism associated with the PLC1 (phospholipase C) locus: identification, mapping, and linkage to the MODY locus on chromosome 20.

A highly polymorphic (dC-dA)n.(dG-dT)n dinucleotide repeat at the PLC1 locus on human chromosome 20 has been identified. Primers flanking the dinucleotide repeat were used for PCR amplification of the repeat region in 37 informative kindreds from the Centre d'Etude du Polymorphisme Humain. Two-point linkage analysis indicates that PLC1 is closely linked to several chromosome 20 markers, including D20S16 (Zmax = 41.25; theta = 0.07), D20S17 (Zmax = 42.81; theta = 0.09), and ADA (Zmax = 57.24; theta = 0.05). Multipoint linkage analysis places the PLC1 locus between D20S18 and D20S17, 11.2 and 6.6 cM, respectively, from these loci (sex-averaged distances). In addition, the PLC1 gene shows linkage to the maturity-onset diabetes of the young (MODY) locus on chromosome 20 with a lod score of 4.57 at theta = 0.089.     

Genetic mapping of autosomal dominant Charcot-Marie-Tooth disease in a large French-Acadian kindred: identification of new linked markers on chromosome 17.

We have performed linkage analysis in a large French-Acadian kindred segregating one form of autosomal dominant Charcot-Marie-Tooth disease (CMTD) (type IA) using 17 polymorphic DNA markers spanning human chromosome 17 and demonstrate linkage to several markers in the pericentromeric region, including DNA probes pA10-41, EW301, S12-30, pTH17.19, c11-2B, and p11-2c11.5. Linkage of markers pA10-41 and EW301 to CMTD type IA has been reported elsewhere. Four new markers, 1516, 1517, 1541, and LL101, which map to chromosome 17 have been identified. The marker 1516 appears to be closely linked to the CMTD locus on chromosome 17 as demonstrated by a maximum lod score of 3.42 at theta (recombination fraction) = 0. This marker has been mapped to 17p11.2 using a somatic cell hybrid constructed from a patient with Smith-Magenis syndrome [46,XY, del(17)(p11.2p11.2)]. A lod score of 6.16 has been obtained by multipoint linkage analysis with 1516 and two markers from 17q11.2, pTH17.19, and c11-2B. The markers 1517 and 1541 have been mapped to 17p12-17q11.2 and demonstrate maximum lod scores of 2.35 and 0.63 at recombination values of .1 and .2, respectively. The marker LL101 has been mapped to 17p13.105-17p13.100 and demonstrates a maximum lod score of 1.56 at a recombination value of .1. Our study confirms the localization of CMTD type IA to the pericentromeric region of chromosome 17.     

Infantile form of neuronal ceroid lipofuscinosis (CLN1) maps to the short arm of chromosome 1.

The neuronal ceroid lipofuscinoses (CLNs) are one of the most common progressive encephalopathies of childhood in Western countries. They are divided into three main types: infantile, late infantile, and juvenile. The inheritance of all forms is autosomal recessive, and the biochemical background is totally unknown. The infantile type (CLN1) demonstrates the earliest onset of symptoms and the most severe clinical course. CLN1 is enriched in the Finnish population with incidence of 1:20,000, and only about 50 cases have been reported from other parts of the world. We have collected 15 Finnish CLN1 families with one or two diseased children for a linkage analysis with polymorphic probes randomly localized on human chromosomes. After studying 42 polymorphic protein and DNA markers, we found definitive proof of linkage with three different probes on the short arm of chromosome 1, with maximum lod scores of 3.38 at theta = 0.00 (0.00-0.08) for D1S57 (pYNZ2), 3.56 at theta = 0.00 (0.00-0.09) for D1S7 (lambda MS1), and 3.56 at theta = 0.00 (0.00-0.11) for D1S79 (pCMM8). With the assignment of the CLN1 gene, our study demonstrates the power of multiallelic VNTR probes in the search for linkage of a rare recessive disorder using limited family material.     

Autosomal dominant retinitis pigmentosa: Localization of a disease gene (RP6) to the short arm of chromosome 6

DNA from members of an Irish pedigree presenting with late onset autosomal dominant retinitis pigmentosa (ADRP) have been typed with a series of genetic markers from chromosome 6p. Positive two-point lod scores have been obtained with five markers (D6S89: theta = 0.10, Z = 3.338; D6S109: theta = 0.10, Z = 3.932; D6S105: theta = 0.00, Z = 6.081; HLA-DRA: theta = 0.00, Z = 4.364; and RDS: theta = 0.00, Z = 5.376). In a series of overlapping multipoint analyses a lod score of 6.6 was obtained, maximizing at HLA-DRA and hence localizing the ADRP gene (RP5) segregating in this pedigree to 6p. These data provide direct evidence for an additional autosomal dominant RP locus and strongly implicate the human equivalent of the mouse retinal degeneration slow (rds) gene, peripherin-rds, as a candidate for autosomal dominant retinitis pigmentosa.     

Confirmation of linkage in von Hippel-Lindau disease

Von Hippel-Lindau (VHL) disease was initially reported to be linked to the RAF1 oncogene (3p25). We have ascertained and sampled two large multigenerational VHL families for linkage studies, in order to confirm the localization of the VHL gene as a prelude to fine mapping studies. The probes used in the analysis were p627 (RAF1) and pHeA12 (thyroid hormone receptor B) (3p24.1-3p22). VHL was analyzed as an autosomal dominant trait with age-dependent penetrance. The maximum lod score combining both families was z(theta) = 2.16 at theta = 0.0 for RAF1 and z(theta) = 2.20 at theta = 0.05 for thyroid hormone receptor B. Multipoint analysis using the RAF1 and thyroid hormone receptor B loci resulted in a peak lod score of 3.1 confirming linkage of VHL to this region of chromosome 3. However, the position of VHL relative to the two loci could not be established with certainty.     

The B subunit of coagulation factor XIII is linked to renin and the Duffy blood group to alpha-spectrin on human chromosome 1

Family linkage studies were used to detect two linkage relationships on human chromosome 1. The B subunit of coagulation factor XIII showed significant linkage to renin with a maximum lod score of 5.071 at a distance of 10 cM. Significant linkage was also shown between the Duffy blood group and alpha-spectrin with linkage results giving a combined lod score of 3.194 at 5 cM.     

Choroideremia is linked to the restriction fragment length polymorphism DXYS1 at XQ13-21.

Choroideremia (McK30310), an X-linked hereditary retinal dystrophy, causes night-blindness, progressive peripheral visual field loss, and, ultimately, central blindness in affected males. The location of choroideremia on the X chromosome is unknown. We have used restriction fragment length polymorphisms from the X chromosome to determine the regional localization of choroideremia by linkage analysis in families with this disease. One such polymorphic locus, DXYS1, located on the long arm (Xq) within bands q13-q21, shows no recombination with choroideremia at lod = 5.78. Therefore, with 90% probability, choroideremia maps within 9 centiMorgans (cM) of DXYS1. Another polymorphic locus, DXS11, located within Xq24-q26, also shows no recombination with choroideremia, although at a smaller lod score of 1.54 (90% probability limit theta less than 30 cM). This linkage with DXS11, a marker that is distal to DXYS1, suggests that the locus for choroideremia is also distal to DXYS1 and lies between these two markers in the region Xq13-q24. These results provide regional mapping for the disease that may be useful for prenatal diagnosis and, perhaps ultimately, for isolating the gene locus for choroideremia.     

Alström syndrome: further evidence for linkage to human chromosome 2p13

Alstr?m syndrome is a rare autosomal recessive disorder characterized by retinal degeneration, sensorineural hearing loss, early-onset obesity, and non-insulin-dependent diabetes mellitus. The gene for Alstr?m syndrome (ALMS1) has been previously localized to human chromosome 2p13 by homozygosity mapping in two distinct isolated populations - French Acadian and North African. Pair-wise analyses resulted in maximum lod (logarithm of the odds ratio) scores of 3.84 and 2.9, respectively. To confirm these findings, a large linkage study was performed in twelve additional families segregating for Alstr?m syndrome. A maximum two-point lod score of 7.13 (theta = 0.00) for marker D2S2110 and a maximum cumulative multipoint lod score of 9.16 for marker D2S2110 were observed, further supporting linkage to chromosome 2p13. No evidence of genetic heterogeneity was observed in these families. Meiotic recombination events have localized the critical region containing ALMS1 to a 6.1-cM interval flanked by markers D2S327 and D2S286. A fine resolution radiation hybrid map of 31 genes and markers has been constructed.     

Genetic dissection of gustatory sensitivity to bitterness (sucrose octaacetate) in mice

Genes implicated in consumption of a bitter compound, sucrose octaacetate (SOA), were investigated using a full genomic scanning strategy. For a 0.1 mM concentration, two QTL reached 5.8 and 6.5 lod scores on chromosomes 2 (77 cM) and 11 (14 cM), respectively. For a 1 mM concentration, the Soa linkage on chromosome 6 (58 cM, lod score 9.4) was replicated, and another QTL was found on chromosome 19 (15 cM, lod score 3.2). Candidacy of previously identified genes in the close vicinity of the peak of the QTL was examined.     

Refinement of the locus for autosomal dominant hereditary gingival fibromatosis (GINGF) to a 3.8-cM region on 2p21

Hereditary gingival fibromatosis (HGF, MIM 135300; approved gene symbol GINGF) is an oral disease characterized by enlargement of gingiva. Recently, a locus for autosomal dominant HGF has been mapped to an 11-cM region on chromosome 2p21. In the current investigation, we genotyped four Chinese HGF families using polymorphic microsatellite markers on 2p21. The HOMOG test provided evidence for genetic homogeneity, with evidence for linkage in four families (heterogeneity versus homogeneity test HOMOG, chi(2) = 0. 00). A cumulative maximum two-point lod score of 5.04 was produced with marker D2S390 at a recombination frequency of θ = 0 in the four linked families. Haplotype analysis localized the hereditary gingival fibromatosis locus within the region defined by D2S352 and D2S2163. This region overlaps by 3.8 cM with the previously reported HGF region. Single-strand conformation polymorphism and sequence analysis of the coding region of cytochrome P450 1B1 (CYP1B1) excluded it as a likely candidate gene.     

Allan-Herndon syndrome. II. Linkage to DNA markers in Xq21.

The original family with the Allan-Herndon type of X-linked mental retardation has been investigated for linkage by using DNA probes spanning the length of the X chromosome. Available for study, over 3 generations, were 13 affected males, three obligate carriers, and three normal sons of the obligate carriers. Initial disease-to-marker analysis suggested linkage to three markers (DXYS2 [7b], DXS250 [GMGX22], and DXS3 [p19-2]) located in Xq21. All three exhibited the same maximum lod score of 2.3 at a maximum theta of .05. Multipoint analysis using LINKMAP and a set of four DNA markers (DXYS1-DXYS2-DXS3-DXS94) gave a multipoint lod score of 3.58 for a location of the Allan-Herndon syndrome near locus DXYS1 (pDP34). Therefore, our data indicate that the gene for the Allan-Herndon syndrome is likely located in Xq21.     

Epidermolysis bullosa: evidence for linkage to genetic markers on chromosome 1 in a family with the autosomal dominant simplex form

DNA from members of a three-generation pedigree of Irish origin, displaying an autosomal dominant simplex form of epidermolysis bullosa of the epidermolytic, simplex, or Koebner variety (EBS2), was analyzed for linkage with a set of markers derived from the long arm of chromosome 1. Two-point analysis revealed positive lod scores for five of these markers, AT3 (Z = 2.107, theta = 0), APOA2 (Z = 1.939, theta = 0.15), D1S66 (Z = 1.204, theta = 0), D1S13 (Z = 1.026, theta = 0.15), and D1S65 (Z = 0.329, theta = 0.15). Multilocus analysis, incorporating the markers D1S19, D1S16, D1S13, APOA2, D1S66, AT3, and D1S65, resulted in a lod score of 3 maximizing at AT3. These data strongly support previous tentative indications of linkage between EBS2 and genetic markers on the long arm of chromosome 1.     

Autosomal dominant aniridia linked to the chromosome 11p13 markers catalase and D11S151 in a large Dutch family

In a large pedigree with autosomal dominant aniridia, we found close linkage between the aniridia locus AN2 and the markers catalase (CAT) (zeta = 7.27 at theta = 0.00) and D11S151 (zeta = 3.86 at theta = 0.10) flanking the AN2 locus on 11p13. Positive lod scores were also obtained for the 11p13----11p14 markers D11S16 and FSHB with the linkage group CAT/AN2/D11S151. We conclude that the autosomal dominant aniridia in this family is due to a mutation at the AN2 locus on 11p13. We have excluded linkage (zeta less than -2 at theta less than 0.18) between the aniridia and the chromosome 2p25 marker D2S1 (linked to ACP1).     

Genetic mapping of DNA segments relative to the locus for the fragile-X syndrome at Xq27.3.

We have tested linkage between the locus for the fragile-X [fra(X)] syndrome at Xq27.3 and five polymorphic restriction sites identified by four DNA probes mapping distal to Xq26.1. A maximum distance of approximately 15 centimorgans (cM) between Xq27.3 and the marker loci mapping to this region was predicted based on the physical chromosome length. Close linkage between the disease and marker loci was excluded for probes DXS19 and DXS37 (theta = .05, Z = -2.94 and Z = -4.17, respectively). These marker loci were estimated to be less than five cM apart but approximately 40 cM proximal to the fragile site, indicating that there is a significantly greater frequency of recombination in this region of the X chromosome than expected from the physical length. Linkage results for the other marker loci and the fra(X) syndrome were inconclusive. However, the pX45d probe locus appears very closely linked to the factor IX locus (Z = 1.94 at theta = 0) and is approximately 20 cM proximal to Xq27.3. A relative map of the polymorphic restriction sites, fra(X) syndrome locus, and factor IX locus was constructed by maximizing lod scores over the Xq26.1----q27.3 region.     

Assignment of X-linked hydrocephalus to Xq28 by linkage analysis

X-linked recessive hydrocephalus (HSAS) occurs at a frequency of approximately 1 per 30,000 male births and consists of hydrocephalus, stenosis of the aqueduct of Sylvius, mental retardation, spastic paraparesis, and clasped thumbs. Prenatal diagnosis of affected males by ultrasonographic detection of hydrocephalus is unreliable because hydrocephalus may be absent antenatally. Furthermore, carrier detection in females is not possible because they are asymptomatic. Using four families segregating HSAS, we performed linkage analysis with a panel of X-linked probes that detect restriction fragment length polymorphisms. We report here that HSAS, in all tested families, is closely linked to marker loci mapping in Xq28 (DXS52, lod = 6.52 at theta of 0.03; F8, lod = 4.32 at theta of 0.00; DXS15, lod = 3.40 at theta of 0.00). These data assign HSAS to the gene-dense chromosomal band Xq28 and allow for both prenatal diagnosis and carrier detection by linkage analysis.     

Localization of the gene for X-linked recessive type of retinitis pigmentosa (XLRP) to Xp21 by linkage analysis.

The X-linked recessive type of retinitis pigmentosa (XLRP) causes progressive night blindness, visual field constriction, and eventual blindness in affected males by the third or fourth decade of life. The biochemical basis of the disease is unknown, and prenatal diagnosis and definitive carrier diagnosis remain elusive. Heterogeneity in XLRP has been suggested by linkage studies of families affected with XLRP and by phenotypic differences observed in female carriers. Localization of XLRP near Xp11.3 has been suggested by close linkage to an RFLP at the locus DXS7 (Xp11.3) detected by probe L1.28. In other studies a locus for XLRP with metallic sheen has been linked to the ornithine transcarbamylase (OTC) locus mapping to the Xp21 region. In this study, by linkage analysis using seven RFLP markers between Xp21 and Xcen, we examined four families with multiple affected individuals. Close linkage was found between XLRP and polymorphic sites OTC (theta = .06 with lod 5.69), DXS84 (theta = .05 with lod 4.08), and DXS206 (theta = .06 with lod 2.56), defined by probes OTC, 754, and XJ, respectively. The close linkage of OTC, 754, and XJ to XLRP localizes the XLRP locus to the Xp21 region. Data from recombinations in three of four families place the locus above L1.28 and below the Duchenne muscular dystrophy (DMD) gene, consistent with an Xp21 localization. In one family, however, one affected male revealed a crossover between XLRP and all DNA markers, except for the more distal DXS28 (C7), while his brother is recombined for this marker (C7) and not other, more proximal markers. This suggests that in this family the XLRP mutation maps near DXS28 and above the DMD locus.     

The Marfan syndrome locus: confirmation of assignment to chromosome 15 and identification of tightly linked markers at 15q15-q21.3

The Marfan syndrome is a common autosomal dominant disorder of connective tissue. Despite many years of intensive investigation, the primary genetic defect has not yet been identified. Reverse genetic methods, targeted at mapping this disease gene, have resulted in an initial report of linkage of the genetic locus for the Marfan phenotype in Finnish families to two polymorphic markers on chromosome 15. We have investigated four large multiplex American families with classic Marfan syndrome using standard genetic linkage methods. Our data confirm the assignment of the Marfan syndrome gene to chromosome 15, but establish a more centromeric location (defined by markers D15S25 and D15S1) as the most probable site for the genetic defect (lod score = 12.1, theta = 0.00). These data should facilitate identification and characterization of the Marfan syndrome gene and, in selected families, have immediate application to diagnosis of equivocal cases or prenatal counseling.