Growth/differentiation factor-5 (GDF5), also known as cartilage-derived morphogenetic protein-1 (CDMP-1), is a secreted signaling molecule that participates in skeletal morphogenesis. Heterozygous mutations in GDF5, which maps to human chromosome 20, occur in individuals with autosomal dominant brachydactyly type C (BDC). Here we show that BDC is locus homogeneous by reporting a GDF5 frameshift mutation segregating with the phenotype in a family whose trait was initially thought to map to human chromosome 12. We also describe heterozygous mutations in nine additional probands/families with BDC and show nonpenetrance in a mutation carrier. Finally, we show that mutant GDF5 polypeptides containing missense mutations in their active domains do not efficiently form disulfide-linked dimers when expressed in vitro. These data support the hypothesis that BDC results from functional haploinsufficiency for GDF5.

We have studied 91 patients with SS genotype, 44 children and 47 adults. Excluding the Cameroon and atypical haplotypes, the distribution in the children's sample exhibited 43% Benin, 38% Bantu, and 3% Senegal. In adults, the sample exhibited 46% Benin, 30% Bantu, and 9% Senegal (chi 2: 13.511, 2 df, P = 0.001). When the whole sample of 198 chromosomes (SS, SC, and S/beta thal) is considered, we find that the beta s chromosome is linked 51% to the Benin haplotype, 41% with the Bantu, and 8% with the Senegal. After adjusting for the different frequencies of beta s in Africa, these numbers would predict the port of origin to be 16% from Atlantic West Africa, 37.3% from Central West Africa, and 46% from Bantu-speaking Africa. This is in direct contradiction with the historical record that establishes a higher percentage from Bantu-speaking Africa (55%) and a much lower percentage from Senegal (3.4%). The overall conclusions from these findings is that there is a loss of Bantu haplotypes in sickle cell syndromes in Cuba, particularly among adults, and that there is an excess of Senegal haplotype, also among adults. These differences might reflect the differential survival and severity of the sickle cell disease linked to these haplotypes.

Twenty-five children with sickle cell disease and repeated episodes of splenic sequestration crises underwent partial splenectomy. They have been followed for 12 to 75 months (median 48 months) after surgery. During this period we have not observed any episode of splenic sequestration and the need for hospitalization and transfusions has been greatly reduced. We believe this is a useful and safe procedure for treating patients with this condition.

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