VH gene usage by family members affected with chronic lymphocytic leukaemia.

The excess risk of chronic lymphocytic leukaemia (CLL) in the first-degree relatives of affected patients suggests that familial CLL might constitute a useful model to study the pathogenesis of this disease, as has been demonstrated in numerous other neoplastic disorders. Previous studies have shown non-random utilization of immunoglobulin genes in CLL, some germline in sequence and others containing numerous somatic mutations. To investigate whether familial cases of CLL exhibit similarities in the composition of the B-cell receptor repertoire to the pattern expressed by CLL patients as a whole, we have studied 25 CLL patients belonging to 12 different families (four French and eight Italian), each of which contained at least two affected members. Among familial cases, VH gene segment utilization proved non-random and diverged from the frequencies previously reported among unrelated patients with CLL. Specifically, although the 4-34 and 5-51 gene segments were found repeatedly, the 1-69 and 4-39 gene segments were used sparingly and the 3-23 gene segment presented with increased frequency. Following the pattern detected in studies of unrelated patients, the single 1-69 expressing CLL contained an unmutated H chain sequence and included a long HCDR3 interval. In contrast, 3-23 containing H chains all used JH4, retained at most 93% homology with germline sequence, and included only short HCDR3 intervals. The vast majority of the CLL variable domains contained a high degree of somatic mutation and exhibited an excess of replacement mutations in the CDR intervals. These findings suggest that familial CLL cases may preferentially derive from B-cell progenitors that have responded to antigen.

Familial Alzheimer's disease (FAD): co-segregation between alleles at the D21S11 DNA marker and the FAD gene in a particular pedigree.

Segregation studies of Alzheimer's disease (AD) gene and a cloned DNA probe (D21S11), which detects an EcoRI restriction fragment length polymorphism for a sequence located in the medial part of the long arm of chromosome 21, are reported in a large pedigree, in which AD is transmitted as an autosomal dominant mendelian trait. In this pedigree, the AD gene co-segregation with one of the alternative alleles at the probe raises the possibility of using such a marker for presymptomatic diagnosis of individuals at risk for the disease.