Brachydactyly, Type E2

A number sign (#) is used with this entry because this form of brachydactyly type E (BDE2) is caused by heterozygous mutation in the PTHLH gene (168470) on chromosome 12p.

For a general phenotypic description and a discussion of genetic heterogeneity of BDE, see BDE1 (113300).

Molecular Genetics

In affected members of a 3-generation family segregating autosomal dominant brachydactyly type E, short stature, and learning difficulties, Klopocki et al. (2010) performed array-based CGH and identified a 907.68-kb microdeletion on chromosome 12p that encompassed 6 known genes, only 1 of which, PTHLH (168470), was known to play a critical role in skeletal development. Klopocki et al. (2010) analyzed the PTHLH gene in 4 unrelated families with BDE and short stature and identified heterozygous missense and nonsense mutations (168470.0001-168470.0004, respectively). None of the affected individuals in the latter 4 families had learning disabilities, suggesting that the deletion of the 5 genes distal to PTHLH most likely accounted for the additional phenotype. Of the 13 total affected individuals, 10 had short stature and 3 were in the normal range. In 2 of the 5 families, affected individuals also had abnormalities of tooth development.

Cytogenetics

In a family with brachydactyly type E (BDE), Maass et al. (2010) identified a t(8;12)(q13;p11.2) translocation with breakpoints upstream of PTHLH on chromosome 12p11.2 and a disrupted KCNB2 (607738) on 8q13. Sequencing of the breakpoints identified a highly conserved activator protein-1 (AP1; see JUN, 165160) motif on 12p11.2, together with a C-ets-1 motif translocated from 8q13. AP1 and C-ets-1 bound in vitro and in vivo at the derivative chromosome 8 breakpoint, but were differently enriched between the wildtype and breakpoint allele. In chondrogenic cells from differentiated fibroblasts from BDE patients, PTHLH and its target genes, ADAMTS7 (605009) and ADAMTS12 (606184), were downregulated along with impaired chondrogenic differentiation. In human and murine chondrocytes, the AP1 motif stimulated PTHLH promoter activity whereas the derivative chromosome 8 breakpoint or C-ets-1 decreased PTHLH promoter activity.