Disease relevance of Holoprosencephaly

• Mice carrying a targeted mutation of Vax1 show dysgenesis of the optic nerve, coloboma, defects in the basal telencephalon, and lobar holoprosencephaly [1].
• These include two loci that cause holoprosencephaly, two that underlie anophthalmia, one of which also contributes to other craniofacial abnormalities such as microcephaly, agnathia, and palatogenesis defects, and one locus responsible for developmental heart and kidney defects [2].
• Transient loss of SHH signaling in the embryonic face inhibits growth of the primordia and results in defects analogous to hypotelorism and cleft lip/palate, characteristics of the mild forms of holoprosencephaly [3].
• Gli2 mutants were found to have abnormal development of maxillary incisors, probably resulting from a mild holoprosencephaly, whereas Gli3 mutants had no major tooth abnormalities [4].
• Microcephaly, sloping forehead, posterior occipital exencephalocele, cerebellar hypoplasia, Chiari malformation, hydrocephalus, polymicrogyria, arhinencephaly, holoprosencephaly and anencephaly constituted a broad spectrum of the reported CNS anomalies [5].

Psychiatry related information on Holoprosencephaly

• This novel TRPC7 gene could be a candidate gene for genetic disorders such as bipolar affective disorder, nonsyndromic hereditary deafness, Knobloch syndrome, and holoprosencephaly, which were mapped to this region [6].

High impact information on Holoprosencephaly

• Mutations in TGIF cause holoprosencephaly and link NODAL signalling to human neural axis determination [7].
• Holoprosencephaly (HPE) is the most common structural defect of the developing forebrain in humans (1 in 250 conceptuses, 1 in 16,000 live-born infants) [7].
• Mutations in the homeodomain of the human SIX3 gene cause holoprosencephaly [8].
• Holoprosencephaly due to mutations in ZIC2, a homologue of Drosophila odd-paired [9].
• Mutations in the human Sonic Hedgehog gene cause holoprosencephaly [10].

Chemical compound and disease context of Holoprosencephaly

• Holoprosencephaly due to mutations in ZIC2: alanine tract expansion mutations may be caused by parental somatic recombination [11].
• The role of cholesterol in Shh signaling and teratogen-induced holoprosencephaly [12].
• Because rats exposed to inhibitors of 7-DHC reductase during development have a high frequency of holoprosencephaly (HPE) [Roux et al., 1979], we have undertaken a search for biochemical evidence of RSH/SLOS and other possible defects of sterol metabolism among patients with various forms of HPE [13].
• We report on 2 sibs with holoprosencephaly of the semilobar type, unusual facial appearance not diagnostic of holoprosencephaly, and primary craniosynotosis involving the coronal and lambdoid sutures [14].
• The malformations could have been caused by the same mechanism as holoprosencephaly after early treatment with AY9944 [15].

Biological context of Holoprosencephaly

• Diminished Sonic Hedgehog (Shh) signaling is associated with the most common forebrain defect in humans, holoprosencephaly (HPE), which includes cyclopia, a phenotype also seen in mice and other vertebrates with defective Shh signaling [16].
• Mutation in human ZIC2, a zinc finger protein homologous to Drosophila odd-paired, causes holoprosencephaly (HPE), which is a common, severe malformation of the brain in humans [17].
• In vitro analysis of partial loss-of-function ZIC2 mutations in holoprosencephaly: alanine tract expansion modulates DNA binding and transactivation [18].
• Meanwhile, it was speculated that the Gli3 gene, mutation of which is responsible for the arhinencephaly in Pdn/Pdn mice, might play a role in mesenchymal programmed cell death during development [19].
• This study describes the epidemiology of holoprosencephaly in a large population, using cases identified through the New York State Congenital Malformations Registry, and born in 1984-1989 [20].

Anatomical context of Holoprosencephaly

• Ectopic bone morphogenetic proteins 5 and 4 in the chicken forebrain lead to cyclopia and holoprosencephaly [21].
• Midline cleft lip and palate was associated not only with growth hormone deficiency (GHD) but also with diabetes insipidus (DI); holoprosencephaly and optic nerve hypoplasia with absence of the septum pellucidum had a similar incidence of GHD and DI [22].
• BACKGROUND AND PURPOSE: Developmental changes in hippocampal formations (HFs) have been reported in association with agenesis of the corpus callosum, lissencephaly, and holoprosencephaly [23].
• We report on a fetus with alobar holoprosencephaly, microphthalmia, midline cleft lip and palate, absent nose, dysplastic ears, radial defects, pentalogy of Fallot, unilateral renal aplasia, absent gallbladder, vertebral anomalies, and absence of ribs [24].
• Holoprosencephaly and thymus hypoplasia observed in diabetic groups were found to be reduced in frequency in the diabetes plus ethanol groups, suggesting an antagonistic type of ethanol-diabetes interaction, stage-dependently [25].

Gene context of Holoprosencephaly

• Finally, based on the chromosomal localization and the expression pattern of the mouse Six3 gene, the human Six3 cognate could be a good candidate to be at least one of the genes affected in patients with holoprosencephaly type 2 due to an interstitial deletion of 2p21-p22 [26].
• Zic5 is located near Zic2, which is responsible for human brain malformation syndrome (holoprosencephaly, or HPE) [27].
• Identification of novel mutations in SHH and ZIC2 in a South American (ECLAMC) population with holoprosencephaly [28].
• Chromosomal localization in mouse and human of the vasoactive intestinal peptide receptor type 2 gene: a possible contributor to the holoprosencephaly 3 phenotype [29].
• Functional characterization of SIX3 homeodomain mutations in holoprosencephaly: interaction with the nuclear receptor NR4A3/NOR1 [30].

Analytical, diagnostic and therapeutic context of Holoprosencephaly

• EEG recognition of holoprosencephaly and Aicardi syndrome [31].
• Sublingual administration of desmopressin. Effectiveness in an infant with holoprosencephaly and central diabetes insipidus [32].
• We reviewed 31 patients (10 females, 21 males) with midline intracranial defects (holoprosencephaly, absence of septum pellucidum, absence of corpus callosum, optic nerve hypoplasia) and correlated the morphology of the hypothalamus with body mass index (BMI), as BMI SDS [33].

References