title: Haploinsufficiency of ALX4 as a potential cause of parietal foramina in the 11p11.2 contiguous gene-deletion syndrome.
abstract: Heterozygous mutations in MSX2 are responsible for an autosomal dominant form of parietal foramina (PFM). PFM are oval defects of the parietal bones that are also a characteristic feature of a contiguous gene-deletion syndrome caused by a proximal deletion in the short arm of chromosome 11 (Potocki-Shaffer syndrome). We have identified a human bacterial artificial chromosome (BAC) clone mapping to chromosome 11, containing a region homologous to the human homeobox gene MSX2. Further sequence analysis demonstrated that the human orthologue (ALX4) of the mouse Aristaless-like 4 gene (Alx4) is contained within this 11p clone. We used FISH to test for the presence-or for the heterozygous deletion-of this clone in two patients with the 11p11.2-deletion syndrome and showed that this clone is deleted in these patients. ALX4 and Alx4 were shown to be expressed in bone and to be absent from all other tissues tested. The involvement of Alx4 in murine skull development, its bone-specific expression pattern, the fact that Alx4 is a dosage-sensitive gene in mice, and the localization of a human genomic clone containing ALX4 to 11p11.2, with hemizygosity in patients with deletion of 11p11.2 who have biparietal foramina, support the contention that ALX4 is a candidate gene for the PFM in the 11p11.2-deletion syndrome.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Y Q
authors.initials: YQ
authors.lastname: Wu
authors.forename: J L
authors.initials: JL
authors.lastname: Badano
authors.forename: C
authors.initials: C
authors.lastname: McCaskill
authors.forename: H
authors.initials: H
authors.lastname: Vogel
authors.forename: L
authors.initials: L
authors.lastname: Potocki
authors.forename: L G
authors.initials: LG
authors.lastname: Shaffer
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001842:Bone and Bones / Q000378:metabolism; D002872:Chromosome Deletion; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics*; D003001:Cloning, Molecular; D004268:DNA-Binding Proteins; D005091:Exons / Q000235:genetics; D017353:Gene Deletion; D008040:Genetic Linkage / Q000235:genetics; D006239:Haplotypes / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D051379:Mice; D008969:Molecular Sequence Data; D009928:Organ Specificity; D010294:Parietal Bone / Q000002:abnormalities*; D020161:Physical Chromosome Mapping; D011506:Proteins / Q000737:chemistry / Q000235:genetics*; D022821:RNA Splice Sites / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016415:Sequence Alignment; D013577:Syndrome; D014157:Transcription Factors
chemical_list: C416676:ALX4 protein, human; D004268:DNA-Binding Proteins; D011506:Proteins; D022821:RNA Splice Sites; D012333:RNA, Messenger; D014157:Transcription Factors