Fig. 2

Genetic variations found in zebrafish bmpr1aa and bmpr1ab genes.

(A) The lin mutation was mapped to a region on chromosome 13 that includes the bmpr1aa gene. (B) T>A basepair change that was found in all lin mutant embryos results in a Leu to Arg change at position 337 (L337R). (C) Crystal structure of human BMPR1B. The kinase domain from the human BMPR1B with the kinase inhibitor LDN-193189 (ball-and-stick representation) bound to the ATP binding site (pdb entry 3MDY). Leu 312 (corresponding to Leu 337 in fish) is shown in red. Structural elements providing residues to the hydrophobic core surrounding Leu 312 are highlighted in dark blue. (D) Detailed view of the hydrophobic core surrounding Leu 312 (in red). Black labels refer to the structure of human BMPR1A, the corresponding residues in fish are indicated by grey italic labels. Consequences of the L312R mutation are analyzed by replacing the leucine side chain in the structure model with arginine, of which five typical rotamers are shown (yellow to green). All rotamers cause serious clashes with surrounding residue, which are highly conserved in fish. (E) C>A basepair change in the bmpr1ab gene that results in a premature stop codon at position 84 in the extracellular domain of the receptor. (F) A MZbmpr1ab mutant embryo at 2 dpf with no obvious phenotypes in the heart or tail region (magnified). (G) Bmpr1a dose-dependent effect on dorsoventral and left-right patterning. Embryos derived from an incross of bmpr1aa+/-bmpr1ab+/- double carrier fish was analyzed and quantified for the dorsoventral phenotypes (classified as C1 (mild) to C4 (strong)) and position of the heart (left or midline) if present. n/a, not applicable since no heart tissue was present.