Genomic Cloning and Characterization of the Human Homeobox Gene SIX6 Reveals a Cluster of SIX Genes in Chromosome 14 and Associates SIX6 Hemizygosity with Bilateral Anophthalmia and Pituitary Anomalies

A new mutation in the six-domain of SIX3 gene causes holoprosencephaly

“…This gene, belonging to the SIX family is closely related to SIX3. 5 In the end the involvement of SIX6 was excluded by two enzymatic digestions. Furthermore, expression of SIX6 in the human embryonic eye starts after 12 weeks of gestation.…”

“…Furthermore, expression of SIX6 in the human embryonic eye starts after 12 weeks of gestation. 5 As human proencephalic brain cleaves into two parts (telencephale and diencephale) at an earlier stage (5 weeks), alterations of SIX6 should not be involved in HPE. In contrast, SIX6 haploinsufficency was described in some anophthalmic patients with pituitary anomalies.…”

“…In contrast, SIX6 haploinsufficency was described in some anophthalmic patients with pituitary anomalies. 5 The identification of this SIX3 mutation made genetic counselling more reassuring for the normal male (II3), who was not a carrier. This SIX3 mutation, found in a panel of 56 unrelated HPE patients, confirms the well-known genetic heterogeneity of the disease, as five mutations were found in SHH, 9,12 three in ZIC2 and a missense mutation in SIX3 (data not shown).…”

“…1 The aetiology is extremely heterogeneous. Among the genetic factors, at least 12 chromosomal loci have been implicated, 2 5 SIX3 has been isolated from the human critical region HPE2 on chromosome 2p21, owing to the existence of the mouse Six3 gene on the homologous distal region of mouse chromosome 17. Mouse Six3 is a homeobox gene expressed in the developing retina, lens, hypothalamus, and pituitary; 6 it has been initially described as sine oculis homologue, a Drosophila gene involved in eye development.…”

“…Expression of SIX3 was detected in eye retina in human embryos at 5-7 weeks of gestation until adulthood. 5 SIX3 was a good candidate gene due to its expression and its map position overlapping the chromosomal region related to HPE2. Thus Wallis et al 8 described four mutations in the homeodomain (one deletion of nine nucleotides and three missense mutations) in patients who had typical HPE facial features.…”