Sunday, March 20, 2016

Holoprosencephaly due to SIX3 mutations

Inspired by a patient with this gene abnormality.

Wallis DE, Roessler E, Hehr U, Nanni L, Wiltshire T, Richieri-Costa A, Gillessen-Kaesbach G, Zackai EH, Rommens J, Muenke M. Mutations in the homeodomain of the human SIX3 gene cause holoprosencephaly.  Nat Genet. 1999 Jun;22(2):196-8.

Holoprosencephaly (HPE) is a common, severe malformation ofthe brain that involves separation of the central nervous system into left andright halves. Mild HPE can consist of signs such as a single central incisor,hypotelorism, microcephaly, or other craniofacial findings that can be presentwith or without associated brain malformations. The aetiology of HPE isextremely heterogeneous, with the proposed participation of a minimum of 12HPE-associated genetic loci as well as the causal involvement of specificteratogens acting at the earliest stages of neurulation. The HPE2 locus wasrecently characterized as a 1-Mb interval on human chromosome 2p21 thatcontained a gene associated with HPE. A minimal critical region was defined bya set of six overlapping deletions and three clustered translocations in HPEpatients. We describe here the isolation and characterization of the humanhomeobox-containing SIX3 gene from the HPE2 minimal critical region (MCR). Weshow that at least 2 of the HPE-associated translocation breakpoints in 2p21are less than 200 kb from the 5' end of SIX3. Mutational analysis hasidentified four different mutations in the homeodomain of SIX3 that arepredicted to interfere with transcriptional activation and are associated withHPE. We propose that SIX3 is the HPE2gene, essential for the development of theanterior neural plate and eye in humans.

Pasquier L, Dubourg C, Blayau M, Lazaro L, Le Marec B, David V, Odent S. A newmutation in the six-domain of SIX3 gene causes holoprosencephaly. Eur J HumGenet. 2000 Oct;8(10):797-800.

Holoprosencephaly (HPE) is a severe brain malformation whichresults from incomplete cleavage of the forebrain during early embryogenesis.The aetiology of HPE is very heterogeneous. Among the genetic factors, SIX3,which is considered to be the functional orthologue of Drosophila genes sineoculis (so) and optix, has been found to be mutated in the homeodomain, in somepatients with HPE (HPE2 on chromosome 2p21). We report a new HPE family,presenting a wide spectrum of clinical features, ranging from cyclopia tohypotelorism, in which a mutation was found for the first time in the SIXdomain of SIX3: a GG insertion creates a frameshift leading to a nonsensemutation downstream in the homeodomain region.

Wallis D, Muenke M. Mutations in holoprosencephaly. Hum Mutat. 2000;16(2):99-108.

Holoprosencephaly (HPE) is the most common developmental defect of the forebrainand midface in humans. In holoprosencephaly the cerebral hemispheres of thebrain fail to separate into distinct left and right hemispheres. This malfor-mation is due to the improper specification and formation of the forebrainduring early development. When one considers the great number and kinds ofgenetic interactions that must occur to properly pattern the developing forebrain, it is not surprising that HPE is extremely heterogeneous. In addition to teratogenicagents, several genes are implicated as the cause of HPE. At least 12 differentloci have been associated  with HPE and now several distinct human genes forholoprosencephaly have been identified. These genes include Sonic Hedgehog (SHH),ZIC2, SIX3, and TG-interacting factor (TGIF). Here we present an overview of thepresently known genes causing human holoprosencephaly. We discuss their functionalrole in development of the forebrain and summarize the mutations and polymorphisms that have been identified within them.

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