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Fibroblast growth factor-8 (Fgf8) is a recently identified growth factor that stimulates the androgen-dependent growth of mouse mammary carcinoma cells. Evidence from mouse development also shows that Fgf8 may play an important role in growth and patterning of limbs, face, and the central nervous system. We describe here the human FGF8 genomic sequence and demonstrate conservation between the human and mouse sequences, including alternatively spliced exons in the mouse. Mapping of FGF8 by FISH using an FGF8-containing bacterial artificial chromosome and by genetic linkage using a SSCP variant identified in this study is also reported and refines the FGF8 map location to 10q24. Since FGF8 maps to the same chromosomal region as FGFR2, has indeed been shown to be a ligand for FGFR2, and has an expression pattern consistent with limb and craniofacial anomalies, we have screened two kindreds with Pfeiffer syndrome that were previously linked to markers from 10q24–25 and a large number of individuals with craniosynostosis and limb anomalies for mutations in the coding sequence of FGF8. While no such mutations were identified, a rare polymorphic variant, consisting of an 18-base-pair (six-amino-acid) duplication in exon 1c, is reported that apparently has no clinical effect. Our exclusionary data suggest that mutations in FGF8 would be, at best, an infrequent cause of such disorders. Am. J. Med. Genet. 72:354–362, 1997. © 1997 Wiley-Liss, Inc.

Rieger syndrome (REG) is an autosomal–dominant human disorder that includes anomalies of the anterior chamber of the eye, dental hypoplasia and a protuberant umbilicus. We report the human cDNA and genomic characterization of a new homeobox gene, RIEG, causing this disorder. Six mutations in RIEG were found in individuals with the disorder. The cDNA sequence of Rieg, the murine homologue of RIEG, has also been isolated and shows strong homology with the human sequence. In mouse embryos Rieg mRNA localized in the periocular mesenchyme, maxillary and mandibular epithelia, and umbilicus, all consistent with RIEG abnormalities. The gene is also expressed in Rathke's pouch, vitelline vessels and the limb mesenchyme. RIEG characterization provides opportunities for understanding ocular, dental and umbilical development and the pleiotropic interactions of pituitary and limb morphogenesis.

Homeobox-containing genes play an important role in development, including positional specification of the body plan and organogenesis. We previously isolated the humanHMX1(H6) gene, a novel homeobox-containing gene of the HMX family, from a human embryonic craniofacial cDNA library. The closely related mouse genesHmx3(Nkx5.1) andHmx2(Nkx5.2) are in the same class as theHMX1gene and are expressed in the craniofacial region of the developing embryo. To provide a resource for further characterization of the humanHMX1gene, we isolated the mouseHmx1genomic clone. We show here the mouseHmx1genomic sequence, its gene mapping, and its expression pattern in the developing mouse embryo. Evidence is presented showing that the three known Hmx genes in the mouse likely play complementary roles in the development of the second arch, retina, sympathetic nerve ganglia, and cranial neural ganglia. Hmx1 may play an important role in the development of craniofacial structures and may interact with Hoxa-2 and Dlx-2 in the second branchial arch.