EVIDENCE FOR LINKAGE OF HUMAN PRIMARY SYSTEMIC CARNITINE DEFICIENCY WITH D5S436 - A NOVEL GENE LOCUS ON CHROMOSOME 5Q

Primary systemic carnitine deficiency (SCD) is a rare hereditary disor der transmitted by an autosomal recessive mode of inheritance. The dis order includes cardiomyopathy muscle weakness, hypoketotic coma with h ypoglycemia, and hyperammonemia. In this study we conducted a linkage analysis of a Japanese SCD family with a proband-a 9-year-old girl-and 26 members. The serum and urinary carnitine levels were determined fo r all members. The entire genome was searched for linkage to the gene locus for SCD, by use of a total of similar to 300 polymorphic markers located similar to 15-20 cM apart. Ln the family, there were two sign ificantly different phenotypes, in terms of serum free-carnitine level s: low serum free-carnitine level (29.5 +/- 5.0 mu M; n = 14) and norm al serum Gee-carnitine level (46.8 +/- 6.2 mu M; n = 12). There was no correlation of urinary free-carnitine levels with the low serum-level phenotype (putative heterozygote), but in normal phenotypes (wild typ e) urinary levels decreased as the serum levels decreased; renal resor ption of free carnitine appeared to be complete in wild-type individua ls, when the serum free-carnitine level was <36 mu M. Linkage analysis using an autosomal dominant mode of inheritance of heterozygosity rev ealed a tight linkage between the disease allele and D5S436 on chromos ome 5q, with a two-point LOD score of 4.98 and a multipoint LOD score of 5.52. The haplotype analysis revealed that the responsible genetic locus lies between D5S658 and D5S434, which we named the ''SCD'' locus . This region was syntenic with the jvs locus, which is responsible fo r murine SCD. Phylogenic conversion of the SCD locus strongly suggests involvement of a single gene, in human SCD.