cM Of Chromosome Research Articles

NCOA3 identified as a new candidate to explain autosomal dominant progressive hearing loss.

Hearing loss is a frequent sensory impairment in humans and genetic factors account for an elevated fraction of the cases. We have investigated a large family of five generations, with 15 reported individuals presenting non-syndromic, sensorineural, bilateral and progressive hearing loss, segregating as an autosomal dominant condition. Linkage analysis, using SNP-array and selected microsatellites, identified a region of near 13 cM in chromosome 20 as the best candidate to harbour the causative mutation. After exome sequencing and filtering of variants, only one predicted deleterious variant in the NCOA3 gene (NM_181659, c.2810C > G; p.Ser937Cys) fit in with our linkage data. RT-PCR, immunostaining and in situ hybridization showed expression of ncoa3 in the inner ear of mice and zebrafish. We generated a stable homozygous zebrafish mutant line using the CRISPR/Cas9 system. ncoa3−/− did not display any major morphological abnormalities in the ear, however, anterior macular hair cells showed altered orientation. Surprisingly, chondrocytes forming the ear cartilage showed abnormal behaviour in ncoa3−/−, detaching from their location, invading the ear canal and blocking the cristae. Adult mutants displayed accumulation of denser material wrapping the otoliths of ncoa3−/− and increased bone mineral density. Altered zebrafish swimming behaviour corroborates a potential role of ncoa3 in hearing loss. In conclusion, we identified a potential candidate gene to explain hereditary hearing loss, and our functional analyses suggest subtle and abnormal skeletal behaviour as mechanisms involved in the pathogenesis of progressive sensory function impairment.

Influence of quantitative trait loci on growth traits of chromosome 1 in Sanjabi lambs during the first year of growth

Abstract This study aimed to detect the quantitative trait loci (QTL) which affecting the growth traits in some parts of chromosomes 1 of Sanjabi lambs. The study population consisted of six groups of fathers which had an average of 39.17 lambs. Initially, the fathers were genotyped for eight microsatellite markers on chromosome 1, and the offspring of the heterozygote fathers were genotyped. The quantitative traits were the body’s weight at birth, 3, 6, 9, and 12 months, which were corrected for the fixed effects of year of birth, sex, and birth type. QTL search was performed by interval mapping based on a regression model for each cM (Centimorgan) of the chromosomes. In total, one QTL in the 235 cM of chromosome 1 was identified from the beginning of the chromosome in associate with weaning weight. The sire substitution effect for both families was 2.14 kg. The confidence interval estimation of the detected QTL that was estimated using the Bootstrap method was 225–238 cM of chromosome 1. This QTL was determined between the MCM137 and MCM130 markers and at a distance of about 9 cM from the MCM137 marker. If this QTL was approved in the next research, it can be used in Marker-assisted selection programs. In this case, more accuracy should be achieved for the evaluation of superior animals.

PARK11 and Gut-microbiota in Parkinson’s disease----- Is there a link?

Parkinson’s disease is a genetically heterogeneous, idiopathic and metacentric neurodegenerative disease of the nervous system characterized by progressive generalized slowing movements like bradykinesia, weakness, tremor, and rigidity, and postural instability in along with Parkinson’s disease has been pondered to be a non-genetic distemper. A different way, features are associated such as sleep dysfunction, loss of smell, mood disorder, constipation, excessive salivation, and excessive periodic limb movements in sleep. Feudatory factors encompass head injury, pesticide exposure, and agriculture background. Results with development and assembling of α- synuclein in the central nervous system in the substantia nigra. A little while back, in North American, Parkinson’s disease is a significant relationship indicated to 39.5cM of chromosome 2 (2q36-37; PARK11) portion on the deep arm. Immune-related disorder, notably Crohn’s and leprosy diseases are also associated with Parkinson’s disease, however around 15% persona with Parkinson’s disease have primary level correlative who has the distemper in the genes including LRRK2, SNCA, last one GBA found as a keek part for sporadic Parkinson’s disease.

Involvement of the Distal Fragment of Chromosome 13 in the Regulation of Sensitivity to Ethanol in Mice

The role of the fragment 57-65 cM of mouse chromosome 13 was studied in the regulation of ethanol action on locomotor activity, anxiety and sensitivity to hypnotic and hypothermic effects of ethanol. We used male mice of recombinant lines AKR/J and AKR.CBA-D13Mit76C, differing only in this fragment. After acute administration of ethanol only AKR mice showed the increase in the length of traveled distance in the open-field test (p < 0.05), only the AKR.CBA-D13Mit76C mice demonstrated the increase the time spent in the center of open-field arena (p < 0.05). Intact animals of both lines did not differ in sleep duration and intensity of hypothermia induced by injections of high doses of ethanol. At the same time, long-term alcohol treatment led to the weakening of the hypnotic effect of ethanol in the males of both lines compared to intact animals (p < 0.01 for the AKR, p < 0.001 for AKR.CBA-D13Mit76C). Chronic alcoholization led to increased ethanol-induced hypothermia in AKR males compared to intact animals (p < 0.01) and did not affect the intensity of ethanol hypothermic effect in AKR.CBA-D13Mit76C mice. The results suggest the involvement of the distal fragment 57-65 cM of chromosome 13 in the mechanisms of ethanol action in mice.

Genome Mining of Rice (Oryza sativa subsp. indica) for Detection and Characterization of Long Palindromic Sequences

Because the rice genome has been sequenced entirely, search to find specific features at genome-wide scale is of high importance for studying genome evolution and subsequent applications. Palindromic sequences are important DNA motifs involved in the regulation of different cellular processes and are a potential source of genetic instability. A genome mining approach was applied to detect and characterize the long palindromic sequences in the rice genome. All palindromes, defined as identical inverted repeats with spacer DNA, could be analyzed and sorted according to their frequency, size, GC content, compact index etc. The results showed that the overall palindrome frequency is high in rice genome (nearly 51000 palindromes), that totally cover 41.4% of nuclear genome of rice, with highest and lowest number of palindromes, respectively belongs to chromosome 1 and 12. Palindrome number could well explain the rice chromosome expansion (R2>92%). Average GC content of the palindromic sequences is 42.1%, indicating AT-richness and hence, the low-complexity of palindromic sequences. The results also showed different compact indices of palindromes in different chromosomes (43.2 per cM in chromosome 8 and 34.5 per cM in chromosome 3, as highest and lowest, respectively). Co-location analysis showed that more than 20% of rice genes overlapped with palindromic regions, mainly concentrating on chromosomal arms. Based on the results of this research it can be concluded that the rice genome is rich in long palindromic sequences that triggered most variation during evolution. Generally, both sections of palindromic sequences including stems and loops are AT-rich, indicating that these regions locate in the low-complexity segments of the rice chromosomes.

Studies of the Relationship between Catalepsy and Anxiety, Aggression, and Depression-Like Behavior Using Congenic Mouse Strains

Catalepsy is a passive-defensive freezing reaction produced in response to threatening stimuli which in exaggerated form constitutes a syndrome of impaired brain function. In mice, the major gene determining susceptibility to catalepsy has been located in the distal 55–75 cM fragment on chromosome 13. Two congenic strains were constructed: AKR.CBA-D13Mit76 and AKR.CBA-D13Mit78, which carry two fragments, i.e., 55–71 and 71–75 cM of chromosome 13, respectively, which were transferred from cataleptic strain CBA to the genome of the non-cataleptic AKR strain. Half of AKR.CBA-D13Mit76 mice were found to show pronounced catalepsy, comparable to that of animals of the donor strain CBA. Decreases in investigative behavior in the open field test were also seen, along with decreases in intermale aggression, as compared with AKR mice, while there were no differences in the forced swimming test. AKR.CBA-D13Mit78 mice showed no differences in comparison with the parent AKR strain in tests for catalepsy, in the open field test, the forced swimming test, or tests for aggression.

Complex traits mapping using introgression lines in pepper (Capsicum annuum).

In this study we used introgression lines of Capsicum annuum to fine map the location of the traits in the chromosome responsible for fruit production, fruit development and fruit ripening. To identify specific regions of the genome for the measurable traits for production, development and ripening in pepper required further investigation using the introgression line approach. Forty-one introgression lines of pepper (C. annum) were used to map the QTLs for fruit production, fruit development and fruit ripening in chromosomes. The traits were evaluated in two glasshouses each with single and double culture cycles. The results confirmed our earlier results that the QTLs for fruit ripening were located at 75 - 100 cM in chromosome 4 and 0 - 100 cM in chromosome 8; QTLs for fruit production at 0 - 100 cM on chromosome 2; QTLs for fruit development at 0 - 50 cM on the chromosome 2 and 0 - 65 cM on chromosome 3. Genotype IL14 had a combination of small and large segments from chromosomes 7 and 10 suggesting that two QTLs were likely involved in the fruit ripening. Statistical analysis was done using genstat Software package. Significant differences (P ≤ 0.05) were found in in some of the lines for the traits tested. Key words: Capsicum annuum, complex trait, mapping, chromosome, production, development, ripening, introgression lines.

A Mammary-Specific, Long-range Deletion on Mouse Chromosome 11 Accelerates Brca1-Associated Mammary Tumorigenesis

We engineered a mammary-specific knockout model for Brca1 deficiency that also lacks the majority of one chromosome 11 to determine whether tumor susceptibility loci reside on this chromosome that cooperate with the loss of Brca1 during mammary cancer formation. Brca1-deficient females that are haploinsufficient in 60 cM of chromosome 11 exhibited accelerated mammary tumorigenesis in comparison to Brca1 conditional knockout mice. On the histopathologic level, these tumors were either adenocarcinomas or benign, inflammatory lesions. Like human BRCA1-associated breast cancers, mammary carcinomas in this new mouse model were ERalpha-negative and of basal epithelial origin. Brca1 deficiency and haploinsufficiency in 60 cM of chromosome 11 caused widespread genome instability as determined by spectral karyotyping analysis. In addition to the verification of the long-range deletion event, the spectral karyotyping analysis revealed that the duplication of the genome and higher degree of aneuploidy occur rather late in tumor progression. Despite chromosomal rearrangements near the Trp53 locus as determined by fluorescence in situ hybridization, the Trp53 gene was transcriptionally active. The analysis of the coding sequence and expression pattern of p53 and p21 suggests that loss-of-heterozygosity of Trp53 caused by somatic mutations contributes to accelerated mammary tumorigenesis in this model.

Microsatellite 의 대립유전자 빈도를 이용한 한우의 경제형질과의 연관성 규명

A total of 10 polymorphic microsatellite markers on bovine chromosome 5 were used for allelic association tests with phenotypic characteristics in Hanwoo. The data analyzed in this study were collected from 326 steers. Chi-square tests were performed to compare the frequencies of individual alleles between the high and the low breeding value groups. The following breeding values were analyzed for QTL effects. The frequency of allele 239 of DIK2828 showed a significant difference between the high and the low breeding value groups in the breeding value of marbling score (MSBV). The allele 279 of BMC1009 was found to show significant differences in allelic distribution for the breeding value of cold carcass weight (CWBV) and the breeding value of backfat thickness (BFBV) and allele 285 showed significant differences in allelic distribution for CWBV, BFBV, and MSBV. The allele 200 of DIK4329 showed significant differences in allelic distributions for the breeding values of longissimus muscle area (LMABV) and BFBV. In this study, we identified the QTL for carcass traits at around 20 (DIK2828), 41 (BMC1009) and 95 (DIK4329) cM in chromosome 5. The results provided a useful reference for further positional candidate gene research and marker-assisted selection for fat metabolism and carcass traits.

Genome‐wide linkage of cotinine pharmacokinetics suggests candidate regions on chromosomes 9 and 11

Characterizing cotinine pharmacokinetics is a useful way to study nicotine metabolism because the same liver enzyme is primarily responsible for the metabolism of both, and the clearances of nicotine and cotinine are highly correlated. We conducted a whole-genome linkage analysis to search for candidate regions influencing quantitative variation in cotinine pharmacokinetics in a large-scale pharmacokinetic study with 61 families containing 224 healthy adult participants. The strongest linkage signal was identified at 135 cM of chromosome 9 with LOD = 2.81 and P = 0.0002; two other suggestive linkage peaks appear at 31.4 and 73.5 cM of chromosome 11 with LOD = 1.96 (P = 0.0013) and 1.94 (P = 0.0014). The confidence level of the linkage between the three genome regions and cotinine pharmacokinetics is statistically significant with a genome-wide empirical probability of P = 0.029.

벼(Oryza sativa L.)의 leuD 유전자

식물의 루이신 생합성에 관여하는 3-isopropylmalate isomerase (IPMI) (EC 4.2.1.33) 효소의 소단편을 암호화는 Leucine D유전자를 벼로부터 분리하고 OsLeuD유전자로 명명하였다. OsLeuD유전자는 257개의 아미노산을 암호화하고 있으며 cyanobacteria의 IPMI 단백질과는 약58% 그리고 green sulfur bacteria들의 IPMI 단백질과는 약48%의 상동성을 갖고 있었다. 벼의 OsLeuD 유전자는 japonica벼 (Oryza sativa L.)의 2번 염색체의 26.45 Mb의 위치로서 109.3 cM 거리에 좌위하고 있었다. OsLeuD유전자는 잎과 성숙하는 종자에 많이 발현이 되었으므로 대사가 급증하는 발생단계 에 발현이 조절되는 것으로 여겨진다. OsLeuD유전자와 단백질은 균류와 yeast 보다 광합성 박테리아의 유전자와 높은 동질성을 보이는 것으로 보아 OsLeuD유전자는 식물의 엽록체 유전자 genome 에서 기원하여 핵 genome으로 이동 진화된 유전자로 추측된다. A rice OsLeuD gene for small subunit of 3-isopropylmalate isomerase (IPMI) (EC 4.2.1.33) has been isolated. OsLeuD gene is located on 109.3 cM of chromosome 2. OsLeuD gene was expressed abundantly in metabolically active organs including leaves and developing seeds, indicating that OsLeuD gene expression is developmentally regulated. The cDNA of OsLeuD gene was coded for 257 amino acids which showed 58% and 48% homology to small subunits of IPMI in OsLeuD genes of cyanobacteria and green sulfur bacteria, respectively. The molecular character of OsLeuD is closely related to those of photosynthetic bacteria rather than those of eukaryotes including fungi and yeast. This suggests that OsLeuD gene in chromosomal genome of plants may possibly be originated from chloroplast genome.

Anthocyaninless1 gene of Arabidopsis thaliana encodes a UDP-glucose:flavonoid-3-O-glucosyltransferase

We isolated several mutants of Arabidopsis thaliana (L.) Heynh. that accumulated less anthocyanin in the plant tissues, but had seeds with a brown color similar to the wild-type. These mutants were allelic with the anthocyaninless1 (anl1) mutant that has been mapped at 15.0 cM of chromosome 5. We performed fine mapping of the anl1 locus and determined that ANL1 is located between the nga106 marker and a marker corresponding to the MKP11 clone. About 70 genes are located between these two markers, including three UDP-glucose:flavonoid-3-O-glucosyltransferase-like genes and a glutathione transferase gene (TT19). A mutant of one of the glucosyltransferase genes (At5g17050) was unable to complement the anl1 phenotype, showing that the ANL1 gene encodes UDP-glucose:flavonoid-3-O-glucosyltransferase. ANL1 was expressed in all tissues examined, including rosette leaves, stems, flower buds and roots. ANL1 was not regulated by TTG1.

Amplified Fragment Length Polymorphism Mapping of Tomato Backcross Populations

Tomato backcross populations of Lycopersicon exculentum cv. Money Maker x Lycopersicon pennellii LA716 were used for construction of an Amplified Fragment Length Polymorphism (AELP) map based on pennellii markers. Ten primer combinations (7 of Eco-Mse and 3 of Pst-Mse) were used. This map spanned 893.7 cM and contained 187 AFLP markers, consisting 130 previously found markers and 57 new markers. A total of 141 markers were found from Eco-Mse primer combination and 46 from Pst-Mse primer combination. The Eco-Mse AFLP markers were not evenly distributed over the chromosomes. The Pst-Mse AFLP markers were found quite frequently and evenly distributed in the more distal part of the chromosomes. Eco-Mse markers were found quite more in numbers in chromosomes 5 and 9, whereas Pst-Mse markers in chromosomes 1 and 7. In chromosomes 4, 6, 7 and 8, the new markers and previously found markers were found quite equal in numbers. The average number of informative markers per primer combination was 18.7 ranging from 6 (E33M47) to 36(E35M48). The average size of map per chromosome was found 74.5 cM ranging from 46.2 cM of chromosome 8 and 105.5 cm of chromosome 3. Fourteen BC1 plants for BC2 and subsequently 12 BC2 plants for BC3 generation were selected to obtain inbred lines with genes of interest. BC1 plants were selected each representing about 50% Lycopersicon pennellii LA716 genome and BC2 plants were selected each representing about 25% genome coverage, and together cover 100% of the Lycopersicon pennellii genome based on scored markers J. Inst. Agric. Anim. Sci. 2003 24:21-28.

Two-Stage Genome-Wide Linkage Scan in Keratoconus Sib Pair Families

To identify susceptibility gene loci for keratoconus. A genome-wide linkage analysis was performed with data from 67 keratoconus sib pair families with 110 affected sib pairs of white or Hispanic origin. A total of 351 subjects were genotyped for 380 microsatellite markers along the genome at approximately 10-cM density. An additional 58 microsatellite markers at approximately 2-cM density in the identified linkage regions on chromosomes 4, 5, 9, 12, and 14 were also genotyped. Multipoint linkage analysis was performed in all pedigrees by nonparametric methods and maximum likelihood estimates of identity by descent sharing as implemented in GeneHunter (http://linkage.rockefeller.edu/soft/gh/ provided in the public domain by Rockefeller University, New York, NY). The strongest evidence of linkage was observed at the telomere (159 cM) of chromosome 9 (lod = 4.5) in all pedigrees. Other regions suggestive of linkage were identified at 176 cM of chromosome 4 (lod = 2.7), 143 cM of chromosome 5 (lod = 2.0), 7 cM of chromosome 9 (lod = 2.8), 12 cM of chromosome 11 (lod = 2.3), 27 cM of chromosome 12 (lod = 2.3), and 14 cM of chromosome 14 (lod = 2.9). Two significant linkage regions were also observed on chromosomes 17 at 86 cM (lod = 3.9) and 9 at 34 cM (lod = 3.8) in the Hispanic subjects only. After fine mapping these regions (with the exception of chromosomes 11 and 17), most linkage peaks remained similar (lod = 2.2 at 176 cM on chromosome 4; lod = 1.7 at 146 cM on chromosome 5; lod = 3.5 at 160 cM on chromosome 9; lod = 2.5 at 7 cM on chromosome 12; and lod = 2.6 at 19 cM on chromosome 14). These results indicate that one or more loci may contribute to keratoconus susceptibility.

Fine mapping of QTLs of chromosome 2 affecting the fruit architecture and composition of tomato

Negative correlations between quality traits and fruit size may hamper the breeding of fresh market tomato varieties for better organoleptic qualities. In a recent QTL analysis, QTLs with large effects on fruit weight, locule number and several quality traits were detected in the distal 50 cM of chromosome 2, but favorable alleles for fruit weight and locule number were unfavorable to quality traits. Substitution mapping was undertaken to determine whether the effects were due to a single QTL or to several tightly linked QTLs. Several chromosomal segments were characterized using near-isogenic lines. Five of them appeared to be involved in one or several traits. Considering the five segments from the top to the bottom of the region, the QTLs detected in each segment controlled the variation of: (1) fruit weight, (2) soluble solids content and dry matter weight, (3) fruit weight, (4) locule number and (5) fruit weight, dry matter weight, total sugars, titratable acidity and soluble solids content. This last cluster illustrates an antagonism between fruit weight and four quality traits, as favorable alleles are not conferred by the same parent in both cases. Nevertheless, several antagonistic QTLs were separated from each other in the first four segments, holding the promise for marker-assisted improvement of fruit quality traits without compromising the fruit size.

Analysis of lung tumorigenesis in chimeric mice indicates the Pulmonary adenoma resistance 2 (Par2) locus to operate in the tumor-initiation stage in a cell-autonomous manner: detection of polymorphisms in the Poli gene as a candidate for Par2.

The Pulmonary adenoma resistance 2 (Par2) locus of the BALB/cByJ mouse, located within 0.5 cM of chromosome 18, is responsible for reducing the mean multiplicity of urethane-induced lung tumors relative to those in C57BL/6J, A/J and C3H/HeJ mice. Thus, BALB/B6-Par2 congenic strain genetically identical to BALB/cByJ except carrying C57BL/6J Par2 alleles develops seven times more tumors than BALB/cByJ. To gain clues for identification of Par2 candidate genes, we analysed lung tumorigenesis in BALB/cByJ<-->BALB.B6-Par2 chimeric animals. Of 100 tumors induced by urethane in 16 chimeras, 82 originated from BALB.B6-Par2 cells, indicating the Par2 phenotype to be cell-autonomous. In addition, the BALB.B6-Par2- and BALB/cByJ-derived tumors were similar in mean size, implying that the phenotype is primarily expressed during initiation rather than in the promotion stage of carcinogenesis. Given these results, we surveyed a comprehensive mouse genome database and physically mapped Par2 within a 2.3 Mbp segment containing three known genes, Poli, Mbd2 and Dcc. Among those, the Poli seemed to be the most reasonable Par2 candidate, since it encodes an extremely error-prone DNA polymerase preferentially incorporating G or T opposite template T in vitro, reminiscent of the Kras2 activation because of an A to G or T point mutation within codon 61 with which most urethane-induced lung tumors are initiated. Indeed, our sequencing of Poli cDNAs from BALB/cByJ, C57BL/6J, A/J and C3H/HeJ lungs revealed 21 BALB/cByJ-specific single-nucleotide polymorphisms in the coding region accompanied by seven amino-acid substitutions and an elevated frequency of alternative splicing, while no polymorphisms associated with tumor susceptibility were found for either Mbd2 or Dcc. Notably, we obtained evidence that BALB/cByJ Par2 alleles may selectively decrease the frequency of Kras2-mutated tumors compared with C57BL/6J alleles. Consequently, the Poli is an intriguing Par2 candidate clearly deserving further evaluation.

Quantitative trait loci on chromosomes 10 and 11 influencing mandible size of SMXA RI mouse strains.

Predicting the mandible size before the termination of growth of the maxillofacial bones is essential in pedodontics as well as for the predictions needed for genetic analysis. Here, Quantitative Trait Locus (QTL) analysis was used to detect the chromosomal regions responsible for the mandible length between the menton and gonion in an SMXA recombinant inbred strain of mice. Around the region 60 cM from the centromere in chromosome 10, the logarithm of the odds score showed a higher than suggestive level. Around the regions 13 cM and 16 cM in chromosome 11, two significant QTLs were detected. Analysis of genotypes from loci corresponding to those QTLs revealed a large mandible when the region between the markers Hba and D11Mit163 and D10Mit70 and D10Mit136 indicated the genotype from the A/J and SM/J alleles, respectively. These results suggest that the major gene(s) responsible for mandible length are located in these regions.

Identification of a new small GTP-binding protein gene OsRab5a, genomic organization, and expression pattern analysis during nitrate supply and early nutrient starvation in rice ( Oryza sativa L .) root

A new nitrate-induced gene OsRab5a in rice was isolated using suppression subtractive hybridization (SSH) method. OsRab5a has 1125 nucleotides with an open reading frame of 612 nucleotides encoding a small GTP-binding protein of Rab family. OsRab5a had a higher expression in root, weak expression in shoot, flower and grain, and visually not in stem and leaf. Southern and mapping analysis indicated that OsRab5a would be a single copy gene at locus of 108.8 cM of chromosome 12. Comparison of genomic organization and tissue distribution showed well-conserved genomic organizations and similar expression patterns between OsRab5a gene in rice and Rha1 gene in Arabidopsis during evolution. OsRab5a was quickly induced by nitrate in a split-root treatment, also up-regulated at early nitrogen and phosphorus starvation in root. Acceleration of root growth was observed under nitrate supply, early nitrogen and phosphorous starvation, which was consistent with the expression pattern of OsRab5a. These results suggest that OsRab5a may function in nutrient-regulated root growth.

Ancestral Founder of Mutation W283X in the Porphobilinogen Deaminase Gene among Acute Intermittent Porphyria Patients

Acute intermittent porphyria (AIP) is a low-penetrant autosomal dominant disorder caused by mutations in the porphobilinogen deaminase gene (PBGD). Nearly 60% of all Swiss AIP patients carry a nonsense mutation W283X (G⁷⁹¹⁶→A). In France, the prevalence of W283X is <5%. To determine whether W283X was a founder mutation or originated from multiple de novo events, we studied 25 apparently unrelated W283X families and index patients, 21 of Swiss and 4 of French origins. In the absence of sufficient genealogical data to verify the ancestral background of these W283X families/patients, we identified haplotypes of seven intragenic single nucleotide polymorphisms (SNPs) in the PBGD gene as well as eight microsatellites flanking the PBGD gene covering 9.88 cM in chromosome 11. Molecular cloning and sequencing experiments were required in order to completely resolve the intragenic haplotypes in this study cohort which mainly consisted of single index patients and families with limited members. Thirteen of the 25 W283X families/patients carry a SNP haplotype [C-A-A-A-G-C-W283X-G] and 12 (including four French families) carry a [T-G-G-G-G-C-W283X-G] haplotype. A less conserved microsatellite haplotype was identified among the 25 W283X alleles which allowed us to estimate the age of the mutation. Since W283X is not explained by a methylcytosine mutation, we favor the hypothesis of a single mutational event which took place on the [T-G-G-G-G-C-G] background at approximately 40 generations or 1000 years ago. Around 550 years ago, a recombination event occurred between intron 3 and 10 of the PBGD gene which resulted in the [C-A-A-A-G-C-W283X-G] haplotype only found in a restricted region.

X‐linked vacuolar myopathies: Two separate loci and refined genetic mapping

X-linked vacuolar myopathies can be divided into two forms: one that is associated with cardiomyopathy and mental retardation (XVCM-MR) and a second form, termed X-linked myopathy with excessive autophagy (XMEA), that spares cardiac muscle and has no central nervous system involvement. In this article, we demonstrate linkage between XMEA and markers on chromosome Xq28 and assign the XMEA gene locus to the most telomeric 10.5 cM of chromosome X. We also show that XVCM-MR is not allelic to XMEA. Ann Neurol 2000;47:666–669