Mutations in the homeobox gene HESX1/Hesx1 associated with septo-optic dysplasia in human and mouse

During early mouse development the homeobox gene Hesx1 is expressed in prospective forebrain tissue, but later becomes restricted to Rathke's pouch, the primordium of the anterior pituitary gland. Mice lacking Hesx1 exhibit variable anterior CNS defects and pituitary dysplasia. Mutants have a reduced prosencephalon, anopthalmia or micropthalmia, defective olfactory development and bifurcations in Rathke's pouch. Neonates exhibit abnormalities in the corpus callosum, the anterior and hippocampal commissures, and the septum pellucidum. A comparable and equally variable phenotype in humans is septo-optic dysplasia (SOD). We have cloned human HESX1 and screened for mutations in affected individuals. Two siblings with SOD were homozygous for an Arg53Cys missense mutation within the HESX1 homeodomain which destroyed its ability to bind target DNA. These data suggest an important role for Hesx1/HESX1 in forebrain, midline and pituitary development in mouse and human.

[1]  Etudes sur les Dysraphies crânio-encéphaliques , 1955 .

[2]  J. Glaser,et al.  Septo-optic dysplasia and pituitary dwarfism. , 1970, Lancet.

[3]  M. Sanders,et al.  Septo-optic Dysplasia , 1972, British medical journal.

[4]  J. C. Vuletin,et al.  A Light and Electron Microscopic Study , 1976 .

[5]  Growth Problems and Clinical Advances. The 1975 Birth Defects Conference Held at Kansas City, Missouri. Daniel Bergsma , R. Neil Schimke , Sue Conde Greene , 1977 .

[6]  D. Becker,et al.  Septo-optic dysplasia: developmental or acquired abnormality? A case report. , 1978, Transactions of the American Neurological Association.

[7]  K. Valentino,et al.  The early formation of the corpus callosum: a light and electron microscopic study in foetal and neonatal rats , 1982, Journal of neurocytology.

[8]  J. Sambrook,et al.  Molecular Cloning: A Laboratory Manual , 2001 .

[9]  W. Rothfus,et al.  Hormonal, metabolic, and neuroradiologic abnormalities associated with septo-optic dysplasia. , 1984, Acta endocrinologica.

[10]  N. Izenberg,et al.  The Endocrine Spectrum of Septo-optic Dysplasia , 1984, Clinical pediatrics.

[11]  P. Strevens.  Iii , 1985 .

[12]  J. R. Moore,et al.  Agenesis of the corpus callosum and macrocephaly in siblings , 1985, Clinical genetics.

[13]  S. Blethen,et al.  Hypopituitarism and septooptic "dysplasia" in first cousins. , 1985, American journal of medical genetics.

[14]  Hypothalamic defects in two adult patients with septo-optic dysplasia. , 1986, Acta endocrinologica.

[15]  E. Small,et al.  Neuropathology of “Septo‐optic Dysplasia” (de Morsier Syndrome) with Immunohistochemical Studies of the Hypothalamus and Pituitary Gland , 1987, Journal of neuropathology and experimental neurology.

[16]  M. Ashburner.  A Laboratory manual , 1989 .

[17]  Septo-optic dysplasia (SOD) or DeMorsier syndrome. , 1989, Journal of clinical neuro-ophthalmology.

[18]  Carl O. Pabo,et al.  Crystal structure of an engrailed homeodomain-DNA complex at 2.8 Å resolution: A framework for understanding homeodomain-DNA interactions , 1990, Cell.

[19]  S. Kelman,et al.  Septo-optic dysplasia in two siblings. , 1990, American journal of ophthalmology.

[20]  P. Gruss,et al.  Pax-6, a murine paired box gene, is expressed in the developing CNS. , 1991, Development.

[21]  R. Lauro,et al.  The transcription factor TTF-1 is expressed at the onset of thyroid and lung morphogenesis and in restricted regions of the foetal brain. , 1991, Development.

[22]  F. Wondisford,et al.  A Mutation in the POU-Homeodomain of Pit-1 Responsible for Combined Pituitary Hormone Deficiency , 1992, Science.

[23]  Matthew H. Kaufman,et al.  The Atlas of Mouse Development , 1992 .

[24]  Andrew P. McMahon,et al.  Sonic hedgehog, a member of a family of putative signaling molecules, is implicated in the regulation of CNS polarity , 1993, Cell.

[25]  M. Fox,et al.  Irradiation hybrids for human chromosome 11: characterization and use for generating region-specific markers in 11q14-q23. , 1993, Genomics.

[26]  M Ptashne,et al.  Determinants of binding-site specificity among yeast C6 zinc cluster proteins. , 1993, Science.

[27]  P. Rathjen,et al.  Hesx1, a homeobox gene expressed by murine embryonic stem cells, maps to mouse chromosome 14, bands A3-B. , 1993, Genomics.

[28]  M. Preece,et al.  Diabetes insipidus with impaired osmotic regulation in septo-optic dysplasia and agenesis of the corpus callosum. , 1994, Archives of disease in childhood.

[29]  [Genomic structure of the homeo box-containing gene XANF1]. , 1994, Doklady Akademii nauk.

[30]  I. Dawid,et al.  Expression pattern of the murine LIM class homeobox gene Lhx3 in subsets of neural and neuroendocrine tissues , 1995, Developmental dynamics : an official publication of the American Association of Anatomists.

[31]  J. Kuriyan,et al.  High resolution crystal structure of a paired (Pax) class cooperative homeodomain dimer on DNA , 1995, Cell.

[32]  J. Rubenstein,et al.  Longitudinal organization of the anterior neural plate and neural tube. , 1995, Development.

[33]  G. Martin,et al.  The mouse Fgf8 gene encodes a family of polypeptides and is expressed in regions that direct outgrowth and patterning in the developing embryo. , 1995, Development.

[34]  N. Copeland,et al.  Six3, a murine homologue of the sine oculis gene, demarcates the most anterior border of the developing neural plate and is expressed during eye development. , 1995, Development.

[35]  P. Rathjen,et al.  Sequence, Genomic Organization, and Expression of the Novel Homeobox Gene Hesx1(*) , 1995, The Journal of Biological Chemistry.

[36]  Interactions of a Rel protein with its inhibitor. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[37]  Further elucidation of the genomic structure of PAX3, and identification of two different point mutations within the PAX3 homeobox that cause Waardenburg syndrome type 1 in two families. , 1995, American journal of human genetics.

[38]  J. Seidman,et al.  A human MSX1 homeodomain missense mutation causes selective tooth agenesis , 1996, Nature Genetics.

[39]  R. Beddington,et al.  Anterior primitive endoderm may be responsible for patterning the anterior neural plate in the mouse embryo , 1996, Current Biology.

[40]  R. Maxson,et al.  The molecular basis of Boston-type craniosynostosis: the Pro148-->His mutation in the N-terminal arm of the MSX2 homeodomain stabilizes DNA binding without altering nucleotide sequence preferences. , 1996, Human molecular genetics.

[41]  A. Simeone,et al.  Germline mutations in the homeobox gene EMX2 in patients with severe schizencephaly , 1996, Nature Genetics.

[42]  O. Quarrell,et al.  Evidence for possible Mendelian inheritance of septo‐optic dysplasia , 1996, Acta paediatrica.

[43]  S. Mackem,et al.  Rpx: a novel anterior-restricted homeobox gene progressively activated in the prechordal plate, anterior neural plate and Rathke's pouch of the mouse embryo. , 1996, Development.

[44]  S. Camper,et al.  The Ames dwarf gene, df, is required early in pituitary ontogeny for the extinction of Rpx transcription and initiation of lineage-specific cell proliferation. , 1996, Molecular endocrinology.

[45]  B. Mosinger,et al.  Specification of Pituitary Cell Lineages by the LIM Homeobox Gene Lhx3 , 1996, Science.

[46]  Wei Wu,et al.  Pituitary lineage determination by the Prophet of Pit-1 homeodomain factor defective in Ames dwarfism , 1996, Nature.

[47]  J. B. Jaynes,et al.  A conserved region of engrailed, shared among all en-, gsc-, Nk1-, Nk2- and msh-class homeoproteins, mediates active transcriptional repression in vivo. , 1996, Development.

[48]  J. Carey,et al.  Cloning and characterization of a novel bicoid-related homeobox transcription factor gene, RIEG, involved in Rieger syndrome , 1996, Nature Genetics.

[49]  J. Rubenstein,et al.  Inductive interactions direct early regionalization of the mouse forebrain. , 1997, Development.

[50]  Stephen W Scherer,et al.  Cone-Rod Dystrophy Due to Mutations in a Novel Photoreceptor-Specific Homeobox Gene ( CRX ) Essential for Maintenance of the Photoreceptor , 1997, Cell.

[51]  J. Collignon,et al.  nodal expression in the primitive endoderm is required for specification of the anterior axis during mouse gastrulation. , 1997, Development.

[52]  J. Smith,et al.  The Xenopus Brachyury promoter is activated by FGF and low concentrations of activin and suppressed by high concentrations of activin and by paired-type homeodomain proteins. , 1997, Genes & development.

[53]  R. Krumlauf,et al.  Axis duplication and anterior identity in the mouse embryo. , 1997, Cold Spring Harbor symposia on quantitative biology.

[54]  A. McMahon,et al.  Evidence that FGF8 signalling from the midbrain-hindbrain junction regulates growth and polarity in the developing midbrain. , 1997, Development.

[55]  M. Boube,et al.  A homeodomain point mutation of the Drosophila proboscipedia protein provokes eye loss independently of homeotic function , 1997, Mechanisms of Development.

[56]  D. Wilson,et al.  Wild-type endoderm abrogates the ventral developmental defects associated with GATA-4 deficiency in the mouse. , 1997, Developmental biology.

[57]  P. Gros,et al.  Reciprocal effect of Waardenburg syndrome mutations on DNA binding by the Pax-3 paired domain and homeodomain. , 1997, Human molecular genetics.

[58]  G. Martin,et al.  An Fgf8 mutant allelic series generated by Cre- and Flp-mediated recombination , 1998, Nature Genetics.

[59]  John A. Phillips,et al.  Mutations in PROP1 cause familial combined pituitary hormone deficiency , 1998, Nature Genetics.

[60]  R. Behringer,et al.  Sequential roles for Otx2 in visceral endoderm and neuroectoderm for forebrain and midbrain induction and specification. , 1998, Development.