We have analyzed DNA marker typing data contributed by six independent groups to estimate the pairwise genetic distances between these markers and the locus for multiple endocrine neoplasia type 2A (MEN 2A). We used LIPED to calculate these distances for female, male, and sex-average linkage maps and to determine the corresponding LOD scores. The preliminary analyses of this large data set (89 MEN 2A families and five non-MEN 2A references families, with 1,934 total individuals) are reported here. These refined estimates of the genetic map in this region will aid in the assignment of presymptomatic diagnoses. This study clearly points out the limitation of pairwise linkage analysis in further refining the position of MEN2A in this small region of chromosome 10. Further refinement of the genetic map position of MEN2A will be best accomplished by finding, verifying, and accurately mapping crossovers in specific families.

We have identified a candidate for the gene responsible for multiple endocrine neoplasia type 2A (MEN 2A) at D10S94 in proximal 10q11.2. An evolutionarily conserved sequence from D10S94 was used as a probe to isolate cDNAs corresponding to a gene that we have termed mcs94-1. The gene spans 11 kb and has an unmethylated CpG island at its 5' end. The mcs94-1 transcript is approximately 2.4 kb in length and is widely expressed. It encodes a putative 415-amino-acid polypeptide that is similar in sequence to nucleolin, an abundant nucleolar protein. Mcs94-1 was examined as a candidate for MEN2A through nucleotide sequence analysis of mcs94-1 exons from an MEN 2A chromosome and its wildtype homologue from an MEN 2A patient. The major portion of the expressed mcs94-1 sequence was examined. No differences in sequence were found between the two alleles.

A physical map for 13 loci on chromosome 10 was developed by determining the dosage of the corresponding DNA sequences in cell lines with unbalanced chromosome 10 rearrangements. Nine of the sequences were assigned to a smaller segment of the chromosome than previously and four sublocalizations were confirmed. The physical map covers most of chromosome 10, from 10p13 to 10q23. The linear order of loci within the physical map agrees with existing linkage maps of chromosome 10. A comparison between the physical map and existing genetic maps indicate an uneven distribution of recombination for chromosome 10. There appear to be hot spots of recombination in the regions defined by q21.1 and q22–q23. In addition, there is a suppression of recombination in the pericentromeric region in males which is not evident in females.

A family segregating for autosomal dominant polycystic kidney disease (ADPKD) is reported. The clinical picture was typical for ADPKD in some family members, although others showed mild involvement. DNA from family members was probed with seven chromosome 16 single-copy DNA sequences that mapped to the telomere of the short arm of the chromosome. The most likely order of six of the probes from the telomere is palpha3'HVR.64 at the designated locus D16S85, CRI-0327 at D16S63, CRI-090 at D16S45, CRI-0129 at D16S56, CRI-0133 at D16S58, and CRI-0136 at D16S60, with the PKD1 locus for ADPKD between D16S85 and D16S63. The seventh probe 24-1 at D16S80 had not been ordered in relation to the other sequences, but PKD1 had been mapped between it and D16S85. The three probes that were informative in our family, palpha3'HVR.64, CRI-090, and CRI-0136 had been linked to the disease locus at recombination frequencies of 4% and approximately 6 and 12%, respectively. Linkage was excluded between the ADPKD locus in our family and palpha3'HVR.64 at a recombination value of up to 6%. Linkage was also excluded between CRI-090 and the disease locus at a recombination value of up to 5%. The data for linkage between CRI-0136 and the ADPKD locus in our family were inconclusive. Multipoint analysis excluded the possibility that the disease in this family lies between the flanking genetic markers that have previously been used to define the genetic interval in which the most common form of polycystic kidney disease, PKD1, lies. We have not made a positive assignment of the ADPKD mutation in this family.(ABSTRACT TRUNCATED AT 250 WORDS)

Journal Article A Pvull RFLP detected by pOB231 at CDC2 on human chromosome 10 Get access N.L. Carson, N.L. Carson Departments of Paediatrics and Biology, Queen's UniversityKingston, Ontario, K7L 3N6, Canada Search for other works by this author on: Oxford Academic PubMed Google Scholar S. Myers, S. Myers Departments of Paediatrics and Biology, Queen's UniversityKingston, Ontario, K7L 3N6, Canada Search for other works by this author on: Oxford Academic PubMed Google Scholar N.E. Simpson N.E. Simpson * Departments of Paediatrics and Biology, Queen's UniversityKingston, Ontario, K7L 3N6, Canada * To whom correspondence should be addressed Search for other works by this author on: Oxford Academic PubMed Google Scholar Nucleic Acids Research, Volume 19, Issue 1, 11 January 1991, Page 196, https://doi.org/10.1093/nar/19.1.196-a Published: 11 January 1991

A refined genetic linkage map for the pericentromeric region of human chromosome 10 has been constructed from data on 12 distinct polymorphic DNA loci as well as the locus for multiple endocrine neoplasia type 2A (MEN 2A), a dominantly inherited cancer syndrome. The map extends from D10S24 (at 10p13–p12.2) to D10S3 (at10q21–q23) and is about 70 cM long. Overall, higher female than male recombination frequencies were observed for this region, with the most remarkable female excess in the immediate vicinity of the centromere, as previously reported. Most of the DNA markers in this map are highly informative for linkage and the majority of the interlocus intervals are no more than 6 cM apart. Thus this map should provide a fine framework for future efforts in more detailed mapping studies around the centromeric area. A set of ordered crossovers identified in this work is a valuable resource for rapidly and accurately localizing new DNA clones isolated from the pericentromeric region.

Combined somatic cell hybrid and linkage studies between D10S94 and five pericentromeric loci (FNRB, D10Z1, MEN2A, RBP3, and D10S15) have localized the new DNA sequence pcl1/A1S-6-c23 at D10S94 to 10q11.2. No recombinants were observed between D10S94 and D10Z1 or MEN2A. D10S94 maps in proximal 10q11.2 very near to MEN2A. There are three possible orders for the six loci that we investigated from the centromeric region of chromosome 10. At present the genetic data do not allow us to order MEN2A with respect to D10Z1 and D10S94. The three possible orders are FNRB-D10Z1-D10S94-MEN2A-RBP3-D10S15, FNRB-D10Z1-MEN2A-D10S94-RBP3-D10S15, and FNRB-MEN2A-D10Z1-D10S94-RBP3-D10S15. In view of the fact that no recombinants between D10S94 and MEN2A or between D10S94 and D10Z1 were observed, the combined haplotypes formed from RFLPs and D10Z1 and D10S94 will increase the informativeness and accuracy of genotype prediction for at-risk members of the families having the MEN 2A syndrome, particularly when the affected parent is female. The localization of D10S94 with respect to MEN2A will prove valuable in experiments directed toward cloning the MEN2A locus.

Journal Article Two Hinfi RFLPs detected by pα10RP8 at D10Z1 Get access Nancy L. Carson, Nancy L. Carson Departments of Paediatrics and Biology, Queen's UniversityKingston, Ontario K7L 3N6, Canada Search for other works by this author on: Oxford Academic PubMed Google Scholar Nancy E. Simpson Nancy E. Simpson * Departments of Paediatrics and Biology, Queen's UniversityKingston, Ontario K7L 3N6, Canada * To whom correspondence should be addressed Search for other works by this author on: Oxford Academic PubMed Google Scholar Nucleic Acids Research, Volume 18, Issue 7, 11 April 1990, Page 1932, https://doi.org/10.1093/nar/18.7.1932 Published: 11 April 1990

Journal Article Three polymorphisms at the D10S85 locus Get access P.J. Goodfellow, P.J. Goodfellow Search for other works by this author on: Oxford Academic PubMed Google Scholar A.R. Brooks-Wilson, A.R. Brooks-Wilson Search for other works by this author on: Oxford Academic PubMed Google Scholar D. Smailus, D. Smailus Search for other works by this author on: Oxford Academic PubMed Google Scholar S. Myers, S. Myers 1Departments of Paediatrics and Biology, Queen's UniversityKingston, Ontario, Canada Search for other works by this author on: Oxford Academic PubMed Google Scholar L. Anderson, L. Anderson 1Departments of Paediatrics and Biology, Queen's UniversityKingston, Ontario, Canada Search for other works by this author on: Oxford Academic PubMed Google Scholar N.E. Simpson N.E. Simpson 1Departments of Paediatrics and Biology, Queen's UniversityKingston, Ontario, Canada Search for other works by this author on: Oxford Academic PubMed Google Scholar Nucleic Acids Research, Volume 18, Issue 16, 25 August 1990, Page 4960, https://doi.org/10.1093/nar/18.16.4960-a Published: 25 August 1990