Syndromic short stature in patients with a germline mutation in the LIM homeobox LHX4

Studies of genetically engineered flies and mice have revealed the role tha t orthologs of the human LIM homeobox LHX4 have in the control of motor-neu ron-identity assignment and in pituitary development. Remarkably, these mou se strains, which bear a targeted modification of Lhx4 in the heterozygous state, are asymptomatic, whereas homozygous animals die shortly after birth . Nevertheless, we have isolated the human LHX4 gene, as well as the corres ponding cDNA sequence, to test whether it could be involved in developmenta l defects of the human pituitary region. LHX4, which encodes a protein 99% identical to its murine counterpart, consists of six coding exons and spans >45 kb of the q25 region of chromosome 1. We report a family with an LHX4 germline splice-site mutation that results in a disease phenotype character ized by short stature and by pituitary and hindbrain (i.e., cerebellar) def ects in combination with abnormalities of the sella turcica of the central skull base. This intronic mutation, which segregates in a dominant and full y penetrant manner over three generations, abolishes normal LHX4 splicing a nd activates two exonic cryptic splice sites, thereby predicting two differ ent proteins deleted in their homeodomain sequence. These findings, which e lucidate the molecular basis of a complex Mendelian disorder, reveal the fu ndamental pleiotropic role played by a single factor that tightly coordinat es brain development and skull shaping during head morphogenesis.