Mutations in the homeodomain of the human SIX3 gene cause holoprosencephaly

Wallis, Deeann; Roessler, Erich; Hehr, Ute; Nanni, Luisa; Wiltshire, Timothy J; Richieri-Costa, Antônio; Gillessen‐Kaesbach, Gabriele; Zackai, Elaine H.; Rommens, Johanna M.; Muenke, Maximilian

doi:10.1038/9718

Cited by 400 publications

(256 citation statements)

References 15 publications

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“…HPE is etiologically heterogeneous, and a number of both environmental and genetic causes have been identified (Muenke and Beachy, 2000;Ming and Muenke, 2002). Mutations in seven genes have been noted to cause human HPE: SHH (Roessler et al, 1996(Roessler et al, , 1997, ZIC2 (Brown et al, 1998), SIX3 (Wallis et al, 1999), TGIF (Gripp et al, 2000), PTCH (Ming et al, 2002b), TDGF1 (De La Cruz et al, 2002), and GLI2 (Roessler et al, 2003). Several other candidate genes for HPE also exist (Kamnasaran et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

TGIF, a gene associated with human brain defects, regulates neuronal development

2006

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-TG-3 -interacting factor (TGIF) is an atypical homeodomain protein.In vitro studies have shown that TGIF can repress transcription mediated by either of two signaling pathways: TGF-␤ and retinoic acid signaling. Mutations in TGIF have been detected in patients with holoprosencephaly (HPE), a severe brain malformation associated with mental retardation. Thus, TGIF must play an essential role in nervous system development. However, the precise function of TGIF during vertebrate neural development is unknown. To investigate the in vivo role of TGIF, we overexpressed TGIF in the developing chick neural tube. Overexpressed TGIF decreased expression of specific genes expressed in dorsally restricted domains of the neural tube, including Cath1, Msx2, Pax6, and Wnt1. In contrast, the expression of other transcription factors, including those necessary for ventral fate such as Nkx2.2, was not affected. Furthermore, a missense mutation in TGIF identified in an HPE patient disrupted the activity of TGIF. In addition, the related protein TGIF2 did not demonstrate the same activity as TGIF. Our data suggest that TGIF plays an important role in regulating the expression of genes expressed in specific dorsal-ventral domains during neural development.

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Section: Introductionmentioning

confidence: 99%

TGIF, a gene associated with human brain defects, regulates neuronal development

2006

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“…For Six genes, inactivation of mouse Six6 is associated with hypogenesis of the pituitary gland and retina (Li et al, 2002). SIX3 mutations in humans cause holoprosencephaly, and Six3 inactivation in mice results in a lack of anterior head structures, including eyes and nose (Wallis et al, 1999;Lagutin et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Six1controls patterning of the mouse otic vesicle

et al. 2004

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A similar gene network was found to control chick myogenesis, in which Six1, Eya2 and Dach2 synergistically regulate the expression of myogenic genes such as myogenin and MyoD (Heanue et Six1 is a member of the Six family homeobox genes, which function as components of the Pax-Six-Eya-Dach gene network to control organ development. Six1 is expressed in otic vesicles, nasal epithelia, branchial arches/pouches, nephrogenic cords, somites and a limited set of ganglia. In this study, we established Six1-deficient mice and found that development of the inner ear, nose, thymus, kidney and skeletal muscle was severely affected. Six1-deficient embryos were devoid of inner ear structures, including cochlea and vestibule, while their endolymphatic sac was enlarged. The inner ear anomaly began at around E10.5 and Six1 was expressed in the ventral region of the otic vesicle in the wild-type embryos at this stage. In the otic vesicle of Six1-deficient embryos, expressions of Otx1, Otx2, Lfng and Fgf3, which were expressed ventrally in the wildtype otic vesicles, were abolished, while the expression domains of Dlx5, Hmx3, Dach1 and Dach2, which were expressed dorsally in the wild-type otic vesicles, expanded ventrally. Our results indicate that Six1 functions as a key regulator of otic vesicle patterning at early embryogenesis and controls the expression domains of downstream otic genes responsible for respective inner ear structures. In addition, cell proliferation was reduced and apoptotic cell death was enhanced in the ventral region of the otic vesicle, suggesting the involvement of Six1 in cell proliferation and survival. In spite of the similarity of otic phenotypes of Six1-and Shh-deficient mice, expressions of Six1 and Shh were mutually independent.

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“…The exons of the HPE genes (SHH, ZIC2, SIX3, and TGIF) and the polydactyly gene, GLI3 were sequenced for mutations as previously described [3,6,11,12,8].…”

Section: Mutation Analysismentioning

confidence: 99%

“…The etiologies of HPE are diverse, comprising genetic [3,6,9,11,12], environmental [5] and cytogenetic factors [1,2]. Dominant de novo mutations and undetected microdeletions have been suggested to account for HPS [4].…”

Section: Introductionmentioning

confidence: 99%

Holoprosencephaly–Polydactyly syndrome: In search of an etiology

Cordero¹,

Bendavid²,

Shanske³

et al. 2008

European Journal of Medical Genetics

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Holoprosencephaly-Polydactyly (HPS) or Pseudotrisomy 13 syndrome are names conferred to clinically categorize patients whose phenotype is congruent with Trisomy 13 in the context of a normal karyotype. The literature suggests that this entity may be secondary to submicroscopic deletions in HPE genes; however a limited number of investigations have been undertaken to evaluate this hypothesis. To test this hypothesis we studied a patient with HPE, polydactyly, and craniofacial dysmorphologies consistent with the diagnosis of Trisomy 13 whose karyotype was normal. We performed mutational analysis in the four main HPE causing genes (SHH, SIX3, TGIF, ZIC2) and GLI3, a gene associated with polydactyly and Fluorescent in-situ hybridization (FISH) to search for microdeletions in these genes and two candidate HPE genes (DISP1 and FOXA2). No mutations or deletions were detected. A whole genome approach utilizing array Comparative Genomic Hybridization (aCGH) to screen for copy number abnormalities was then taken. No loss or gain of DNA was noted. Although a single case, our results suggest that coding mutations in these HPE genes and copy number anomalies may not be causative in this disorder. Instead, HPS likely involves mutations in other genes integral in embryonic development of the forebrain, face and limbs. Our systematic analysis sets the framework in which to study other affected children and delineate the molecular etiology of this disorder.

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Mutations in the homeodomain of the human SIX3 gene cause holoprosencephaly

Cited by 400 publications

References 15 publications

TGIF, a gene associated with human brain defects, regulates neuronal development

TGIF, a gene associated with human brain defects, regulates neuronal development

Six1controls patterning of the mouse otic vesicle

Holoprosencephaly–Polydactyly syndrome: In search of an etiology

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