Notomelia and related neural tube defects in a baby born in Niger: case report and literature review.

INTRODUCTION: Notomelia associated with neural tube defects are rare diseases. CASE REPORT: A baby was born in Niger with multiple congenital embryonic malformations on the posterior midline. The most rostral malformation was an accessory limb (polymelia) at the level of the lumbar vertebrae composed of two long bones, a foot and three toes. Accessory male genitalia were present at the base of this malformed accessory limb which had no apparent motor or sensory innervation. The second malformation was a sacral vestigial appendage with an adjacent dermal sinus opening onto the posterior midline and extending internally to the dura through a defect of the vertebral arches. From the published literature and this particular case, we conclude that notomelia is a rare clinical sequela of a neural tube defect (NTD) and is correctly classified as a dysraphic appendage. CONCLUSION: The recent occurrence of three similar cases in the same ethnic group from Niger, three from consanguineous parents, suggests that genetic factors are likely to contribute significantly to the genesis of this syndrome, consistent with a recent report that mutation of the bovine NHLRC2 gene resulting in a V311A substitution at a highly conserved locus in the NHLRC2 protein is, when homozygous, causally associated with several forms of polymelia including notomelia, with heteropagus conjoined twinning and with other NTD-related embryonic malformations. Detailed genome-wide studies of children with dysraphic appendages are indicated.

High-resolution comprehensive radiation hybrid maps of the porcine chromosomes 2p and 9p compared with the human chromosome 11.

We are constructing high-resolution, chromosomal 'test' maps for the entire pig genome using a 12,000-rad WG-RH panel (IMNpRH2(12,000-rad))to provide a scaffold for the rapid assembly of the porcine genome sequence. Here we present an initial, comparative map of human chromosome (HSA) 11 with pig chromosomes (SSC) 2p and 9p. Two sets of RH mapping vectors were used to construct the RH framework (FW) maps for SSC2p and SSC9p. One set of 590 markers, including 131 microsatellites (MSs), 364 genes/ESTs, and 95 BAC end sequences (BESs) was typed on the IMNpRH2(12,000-rad) panel. A second set of 271 markers (28 MSs, 138 genes/ESTs, and 105 BESs) was typed on the IMpRH(7,000-rad) panel. The two data sets were merged into a single data-set of 655 markers of which 206 markers were typed on both panels. Two large linkage groups of 72 and 194 markers were assigned to SSC2p, and two linkage groups of 84 and 168 markers to SSC9p at a two-point LOD score of 10. A total of 126 and 114 FW markers were ordered with a likelihood ratio of 1000:1 to the SSC2p and SSC9p RH(12,000-rad) FW maps, respectively, with an accumulated map distance of 4046.5 cR(12,000 )and 1355.2 cR(7,000 )for SSC2p, and 4244.1 cR(12,000) and 1802.5 cR(7,000) for SSC9p. The kb/cR ratio in the IMNpRH2(12,000-rad) FW maps was 15.8 for SSC2p, and 15.4 for SSC9p, while the ratio in the IMpRH(7,000-rad) FW maps was 47.1 and 36.3, respectively, or an approximately 3.0-fold increase in map resolution in the IMNpRH(12,000-rad) panel over the IMpRH(7,000-rad) panel. The integrated IMNpRH(12,000-rad) andIMpRH(7,000-rad) maps as well as the genetic and BAC FPC maps provide an inclusive comparative map between SSC2p, SSC9p and HSA11 to close potential gaps between contigs prior to sequencing, and to identify regions where potential problems may arise in sequence assembly.

A single-base change in the tyrosine kinase II domain of ovine FGFR3 causes hereditary chondrodysplasia in sheep.

Ovine hereditary chondrodysplasia, or spider lamb syndrome (SLS), is a genetic disorder that is characterized by severe skeletal abnormalities and has resulted in substantial economic losses for sheep producers. Here we demonstrate that a non-synonymous T>A transversion in the highly conserved tyrosine kinase II domain of a positional candidate gene, fibroblast growth factor receptor 3 (FGFR3), is responsible for SLS. We also demonstrate that the mutant FGFR3 allele has an additive effect on long-bone length, calling into question the long-standing belief that SLS is inherited as a strict monogenic, Mendelian recessive trait. Instead, we suggest that SLS manifestation is determined primarily by the presence of the mutant FGFR3 allele, but it is also influenced by an animal's genetic background. In contrast to FGFR3 mutations causing dwarfism in humans, this single-base change is the only known natural mutation of FGFR3 that results in a skeletal overgrowth phenotype in any species.

Phylogenomic analysis of the alpha proteasome gene family from early-diverging eukaryotes.

We employed a phylogenomic approach to study the evolution of alpha subunits of the proteasome gene family from early diverging eukaryotes. BLAST similarity searches of the Giardia lamblia genome identified all seven alpha proteasome genes characteristic of eukaryotes from the crown group. In addition, a PCR strategy for the amplification of multiple alpha subunit sequences generated single alpha proteasome products for representatives of the Kinetoplastida (Leishmania major), the Parabasalia (Trichomonas vaginalis), and the Microsporidia (Vairimorpha sp., Nosema sp., Endoreticulata sp., and Spraguea lophii). The kinetoplastid Trypanosoma cruzi and the eukaryote crown group Acanthamoeba castellanii yielded two distinct alpha proteasome genes each. The presence of seven distinct alpha proteasome genes in G. lamblia, one of the earliest-diverging eukaryotes, indicates that the alpha proteasome gene family evolved rapidly from a minimum of one gene in Archaea to seven or more in Eukarya. Results from the phylogenomic analysis are consistent with the idea that the Diplomonida (as represented by G. lamblia), the Kinetoplastida, the Parabasalia, and the Microsporidia diverged after the duplication events that originated the alpha proteasome gene family. A model for the early origin and evolution of the proteasome gene family is presented.

Localization of the locus causing Spider Lamb Syndrome to the distal end of ovine Chromosome 6.

Spider Lamb Syndrome (SLS) is a semi-lethal congenital disorder, causing severe skeletal abnormalities in sheep. The syndrome has now been disseminated into several sheep breeds in the United States, Canada, and Australia. The mode of inheritance for SLS is autosomal recessive, making the identification and culling of carrier animals difficult due to their normal phenotype. Two large pedigrees segregating for the SLS mutation were established, and a genome scan with genetic markers from previously published genome maps of cattle and sheep was used to map the locus causing SLS. Genetic linkage between SLS and several microsatellite markers, OarJMP8, McM214, OarJMP12, and BL1038, was detected, thereby mapping the SLS locus to the telomeric end of ovine Chromosome (Chr) 6. Alignment of ovine Chr 6 with its evolutionary ortholog, human Chr 4, revealed a positional candidate gene, fibroblast growth factor receptor 3 (FGFR3).

Genetic mapping of five human chromosome 4 orthologues to bovine chromosomes 6 and 17.

Five loci that map to human chromosome 4 (HSA4) were selected to expand the bovine comparative linkage map. Loci included b-casein (CSN2), basic fibroblast growth factor (FGF2), immunoglobulin J chain (IGJ), interleukin 2 (IL2) and microsomal triglyceride transfer protein (MTTP). Polymorphisms for each locus were identified by either polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) or single-strand conformational polymorphism (SSCP) analysis. The bovine genes for CSN2, IGJ and MTTP were mapped by linkage analysis to chromosome 6; FGF2 and IL2 mapped to chromosome 17. These data refine a position of chromosomal evolution to a small region between FGF2 and the previously mapped complement I factor (IF).

A genetic map of nine loci on bovine chromosome 2.

A male-specific genetic linkage map of nine loci on bovine Chromosome (Chr) 2 (BTA2) was constructed from 306 offspring belonging to six paternal half-sib families. Loci studied were the structural genes for liver/bone/kidney alkaline phosphatase (ALPL). Gardner-Rasheed feline sarcoma (v-fgr) oncogene homolog (FGR), alpha-L-fucosidase 1 (FUCA1), and fibronectin 1 (FN1), and the microsatellite loci ARO28, DU17S2, DU17S3, DU17S4, and DU17S5. Genotyping was performed by restriction fragment length polymorphism (RFLP) for structural genes and polymerase chain reaction (PCR) for the microsatellites. Two genetically independent linkage groups were identified. The order of genes in the first linkage group, L31, is (ARO28-FN1)-FGR-FUCA1-ALPL, covering a map distance of 34.1 cM between terminal markers. The second linkage group, L32, consists of DU17S2-DU17S5-DU17S4-DU17S3 and is 41.3 cM in length. Genetic linkage between FN1 and FGR confirms previous physical assignment of these genes to the same synteny group. Currently, the genetic linkage of FN1 and FGR is unique to cattle and thus localizes a site of chromosomal evolution to a 22-cM interval between the two loci.

Linkage relationships between ALPL, ENO1, GPI, PGD, and TGFB1 on porcine chromosome 6.

A five-point linkage map has been established between the loci encoding liver/bone/kidney alkaline phosphatase (ALPL), enolase 1-alpha (ENO1), glucose-phosphate isomerase (GPI), phosphogluconate dehydrogenase (PGD), and transforming growth factor beta 1 (TGFB1) in swine. Linkage analysis was performed using the Meishan x Yorkshire three-generation reference pedigree at the University of Illinois (n = 91). Previously ENO1, GPI, PGD, and TGFB1 were mapped to porcine chromosome 6q by in situ hybridization but the linkage relations of TGFB1 and ENO1 with other loci in this group were not investigated. Based on mapping data from human chromosomes 1 and 19 and mouse chromosomes 4 and 7, it was postulated that ALPL should reside among or near these loci. Restriction fragment length polymorphisms were identified for ALPL, ENO1, and TGFB1. GPI (EC 5.3.1.9) and PGD (EC 1.1.1.44) phenotypes were determined by agarose gel electrophoresis of isozymes. Marker data were analyzed using the MLINK (two locus) and ILINK (multilocus) programs from LINKAGE (version 5.10). The most likely locus order between GPI-TGFB1-(PGD-ENO1)-ALPL with recombination rates of 0.049, 0.044, 0.000, and 0.156, respectively, could not be significantly determined. The maximum five-point lod score was the same to four decimal places irrespective of the order of ENO1 and PGD. This indicates that ENO1 and PGD are very closely linked and that ALPL is located telomeric to the established linkage group on pig chromosome 6.

Detection of linkage between genetic markers and genes that affect growth and carcass traits in pigs.

Segregation of paternal marker alleles in the progeny of a single boar was used to estimate linkage between the marker genes and associations of these genes with quantitative trait loci (QTL). The sire was heterozygous at four polymorphic marker loci, haptoglobin (HP), glucosephosphate isomerase (GPI), phosphogluconate dehydrogenase (PGD), and esterase D (ESD), and sired 30 litters during an 8-mo period. Glucosephosphate isomerase and PGD were linked (theta = .09; P less than .005). The phase of these two loci in the sire was determined to be GPI A-PGD B, GPI B - PGD A. NO other linkages were detected. Growth (135 less than or equal to n less than or equal to 172) and carcass data (70 less than or equal to n less than or equal to 80) were analyzed assuming a fixed linear model. Least squares means were compared for differences in growth and carcass traits between pigs that inherited alternative paternal marker alleles. Pigs that inherited the GPI A allele from the sire had a 22-g higher daily live weight gain postweaning and reached 103 kg live weight in 2.6 fewer days than did pigs that inherited the GPI B allele (P less than .05), indicative of the presence of gene(s) that affect rate of gain linked to the GPI locus. Pigs that inherited the PGD B allele had a .14 unit higher score for muscle firmness (score ranged from 1 to 3 units) than pigs that inherited the PGD A allele (P less than .05). Pigs that inherited the HP 3 allele had a .06-kg higher weaning weight and a .11 lower ham muscle mass score than did pigs that inherited the HP 2 allele from the sire (P less than .05). No associations with quantitative traits were detected for ESD.