Von Hippel-Lindau-dependent polycythemia is endemic on the island of Ischia: identification of a novel cluster.
Chuvash polycythemia (MIM 263400) is an autosomal recessive disorder characterized by a high hemoglobin level, relatively high serum erythropoietin, and early death. It results from a Von Hippel-Lindau (VHL) gene mutation (C598T) that causes increased HIF-1alpha activity and erythrocyte production in the face of normoxia. This polycythemia is endemic in Chuvashia, whereas its worldwide frequency is very low. We investigated the incidence of the Chuvash-type VHL mutation in Campania (South Italy) and identified 14 affected subjects (5 families). Twelve live on the island of Ischia (Bay of Naples). From analysis of the mutated allele, we found that the disease was more frequent on Ischia (0.070) than in Chuvashia (0.057). The haplotype of all patients matched that identified in the Chuvash cluster, thereby supporting the single-founder hypothesis. We also found that nonaffected heterozygotes had increased HIF-1alpha activity, which might confer a biochemical advantage for mutation maintenance. In conclusion, we have identified the first large cluster of Chuvash erythrocytosis outside Chuvashia, which suggests that this familial polycythemia might be endemic in other regions of the world.
Perrotta
Silverio
S
Department of Pediatrics, Second University of Naples, Via Luigi De Crecchio, 4, Naples, Italy. silverio.perrotta@unina2.it
Nobili
Bruno
B
Ferraro
Marcella
M
Migliaccio
Carmela
C
Borriello
Adriana
A
Cucciolla
Valeria
V
Martinelli
Vincenzo
V
Rossi
Francesca
F
Punzo
Francesca
F
Cirillo
Paola
P
Parisi
Giuseppe
G
Zappia
Vincenzo
V
Rotoli
Bruno
B
Della Ragione
Fulvio
F
D000328:Adult; D002461:Cell Line, Transformed; D002648:Child; D004252:DNA Mutational Analysis; D005260:Female; D005843:Geography; D006239:Haplotypes / Q000235:genetics; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D000860:Hypoxia / Q000235:genetics / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007558:Italy; D008214:Lymphocytes / Q000166:cytology / Q000378:metabolism; D008297:Male; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D011086:Polycythemia / Q000235:genetics* / Q000378:metabolism; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics*
C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human