Chorea-acanthocytosis (CHAC) is a rare autosomal recessive disorder characterized by progressive neurodegeneration and unusual red-cell morphology (acanthocytosis), with onset in the third to fifth decade of life. Neurological impairment with acanthocytosis (neuroacanthocytosis) also is seen in abetalipoproteinemia and X-linked McLeod syndrome. Whereas the molecular etiology of McLeod syndrome has been defined (Ho et al. 1994), that of CHAC is still unknown. In the absence of cytogenetic rearrangements, we initiated a genomewide scan for linkage in 11 families, segregating for CHAC, who are of diverse geographical origin. We report here that the disease is linked, in all families, to a 6-cM region of chromosome 9q21 that is flanked by the recombinant markers GATA89a11 and D9S1843. A maximum two-point LOD score of 7.1 (theta = .00) for D9S1867 was achieved, and the linked region has been confirmed by homozygosity-by-descent, in offspring from inbred families. These findings provide strong evidence for the involvement of a single locus for CHAC and are the first step in positional cloning of the disease gene.

The haemochromatosis gene (HFE) is linked to both HLA-A and D6S105 on the short arm of chromosome 6 but these markers are separated by approximately 2 Mb of DNA. Most chromosomes carrying HFE have a common haplotype which extends from HLA-A to D6S105 and includes HLA-F. To localise the gene more precisely we have examined 10 microsatellite markers extending over a genetic distance of approximately 5 cM from D6S265 (within 100 kb of HLA-A on the centromeric side) to D6S299 (telomeric). The order of markers is D6S265, HLA-F, D6S258, D6S306, CS3, D6S105, D6S464, CS5, D6S461 and D6S299. We confirm that haemochromatosis appears to originate from a founder mutation which has multiplied in the population through successive generations. This mutation is associated with the haplotype D6S306-5, CS3-3, D6S105-8, D6S464-9 and CS5-4 which is found on approximately 70% of HFE chromosomes. We have applied a new and powerful, likelihood analysis for linkage disequilibrium. The maximum value of lambda (proportion of total possible association between a marker and disease) is 0.74 for marker CS5 (allele 4). A multipoint analysis also gives a maximum likelihood near marker CS5. We conclude that the HFE gene is likely to be located telomeric of D6S105 and close to CS5.

The 22 antigens of the Kell blood group system are located on a red blood cell (RBC) membrane glycoprotein that shows sequence homology with a family of metalloendopeptidases. Expression of the Kell system antigens is partially governed by XK, an X-linked gene that encodes the Kx protein; absence of Kx results in reduced Kell antigen expression. Almost total absence of Kell antigens from the RBCs of a German man with no symptoms of neuroacanthocytosis could not be due to the Kell- null phenotype, Ko, because his RBCs had very weak expression of Kx antigen and his three children were Kp(a + b+). Kell antigens were normal on the RBCs of his son but weak on those of his two daughters. An Nla III restriction fragment-length polymorphism within the KEL gene showed the Kpa/Kpa genotype in the propositus. Sequencing of his XK gene showed a single base change within the donor splice consensus sequence of intron 2. A BsaAl restriction fragment-length polymorphism showed the mutation in both of his daughters but not in his son. The extreme depression of the Kell antigens of the propositus must be due to a combination of effects, ie, homozygosity for Kpa and deficiency of Kx protein, each of which is capable of causing some degree of weakening of Kell antigens.

of the hemochromatosis-linked HLA allele, HLA-A3, and The cause of the hepatic siderosis and iron overload PCT 7-9 but not by others. [10][11][12][13] Recently it has been shown that that is common in porphyria cutanea tarda (PCT) is unthe hemochromatosis gene (HFE) is most likely located close certain. Heterozygosity for genetic hemochromatosis to the microsatellite DNA marker, D6S1260 (formerly CS5), has been supported by some studies of the association which is 700kb telomeric to the marker D6S105, which is between the HLA-A3 antigen and porphyria cutanea itself 2-3 cm telomeric to the HLA-A locus. The cause of the hepatic siderosis and mild iron overload a denaturing gel.14 For D6S1260 one primer was labelled with [g-that is common in PCT is uncertain. The hypothesis that it 32 P]adenosine triphosphate using T4 polynucleotide kinase; the polyis caused by heterozygosity for genetic hemochromatosis merase chain reaction products were denatured, fractionated by elec-(GH) 7 has been supported by some studies of the association trophoresis in polyacrylamide gels under denaturing conditions, and visualised by autoradiography.14 Statistical Analysis. Allele frequencies were determined by direct counting and individuals possessing a single allele were assumed to Abbreviations: PCT, porphyria cutanea tarda; GH, genetic hemochromatosis; HFE, hebe homozygous for that allele. The significance of differences between Other Methods. Transferrin saturation was calculated from the Received May 15, 1996; accepted August 29, 1996. concentrations of plasma iron, measured by atomic absorption spec-