Contiguous gene deletion within chromosome arm 10q is associated with juvenile polyposis of infancy, reflecting cooperation between the BMPR1A and PTEN tumor-suppressor genes

Abstract

We describe four unrelated children who were referred to two tertiary referral medical genetics units between 1991 and 2005 and who are affected with juvenile polyposis of infancy. We show that these children are heterozygous for a germline deletion encompassing two contiguous genes, PTEN and BMPR1A. We hypothesize that juvenile polyposis of infancy is caused by the deletion of these two genes and that the severity of the disease reflects cooperation between these two tumor-suppressor genes.

Figure 1

Deletion of the PTEN and BMPR1A loci evidenced by FISH in patient 2. A, PTEN FISH. The hybridization of BAC RP11-60C5 (green) and control probe (YAC 889C10, 10qtel) (red) shows, in one chromosome copy, the lack of the BAC RP11-60C5 signal, indicating the heterozygous deletion of the PTEN locus. B, Scheme of BAC RP11-411A19 hybridization on chromosome arm 10q. BAC RP11-411A19 contains the BMPR1A gene. The specific signal encompassing the BRMR1A locus is located in 10q23. In addition to the specific signal, a major cross-hybridization signal was detected in 10q11.2. When the specific hybridization signal is missing, a second, minor cross-hybridization signal appears. It is due to a 25-kb region located 13 Mb centromeric to BMPR1A, which presents 96% homology with a region of BAC RP11-411A19. C, BMPR1A FISH. The major cross-hybridization signal of BAC RP11-411A19, centromeric to the specific signal, was used as control (arrows a and d). The specific signal (arrow c) appears largely decreased in one chromosome (arrow b), suggesting the complete or partial deletion of the BMPR1A gene. As mentioned above, the remaining signal is due to a second cross-hybridization (arrow b).

Figure 2

Deletion breakpoints of patients 1 and 2. A, Scheme of the physical map of the 10q23 region. B, Genes located in the regions of deletion. C, Main BACs used for FISH. Deleted BACs are red; undeleted BACs are green. D, Junction points defined in patients 1 and 2. For patient 1, the proximal breakpoint is located 2.5 kb upstream of the BMPR1A coding sequence (chromosome position 88623207), and the telomeric breakpoint is located 5 kb downstream of the ACTA2 gene (chromosome position 90706778). For patient 2, the proximal breakpoint is located in intron 1 of LDB3 (chromosome position 88421964), and the telomeric breakpoint is located 19 kb downstream of the LIPF gene (chromosome position 90446243).