Sonic Hedgehog (SHH) and GLI2, an obligatory mediator of SHH signal transduction, are holoprosencephaly (HPE)-associated genes essential in pituitary formation.
These functions are very likely conserved among bilaterians since vertebrate six3 is required for neuroendocrine and median brain development with certain mutations leading to holoprosencephaly.
Holoprosencephaly (HPE) is genetically heterogeneous with four genes, SIX3, SHH, TGIF, and ZIC2 that have been identified to date and that are altered in 12% of patients.
Mutations in GLI2 have been found in association with holoprosencephaly (HPE) and HPE-like phenotype, with and without pituitary hormone deficiencies; as well as in patients with pituitary dysfunction with and without HPE craniofacial features.
This usually includes analysis of chromosomes by high-resolution karyotyping, clinical assessment to rule-out well recognized syndromes that are associated with HPE (e.g., Pallister-Hall syndrome, Smith-Lemli-Opitz syndrome and others), and molecular studies of the most common HPE associated genes (e.g., SHH, ZIC2 and SIX3).
Utilizing prospective sequence analysis of SHH, ZIC2, SIX3 and TGIF in holoprosencephaly probands to describe the parameters limiting the observed frequency of mutant gene×gene interactions.
Numerous genetic loci and environmental factors are implicated in HPE, but mutation in the sonic hedgehog (Shh) gene is an established cause in both humans and mice.
Our data indicate that in a subset of patients SCH may develop as one aspect of a more complex malformation of the ventral forebrain, directly result from mutations in the SHH pathway and hence be considered as yet another feature of the broad phenotypic spectrum of holoprosencephaly.
However, the family presented here is unique as none of the three identified individuals with a GLI2 deletion showed any typical signs of holoprosencephaly, whereas all patients reported so far were referred for genetic testing because at least one member exhibited holoprosencephaly and related features.
We hypothesize that mutations of a gene in 7q36, designated HPE3, are responsible for both sporadic HPE and a majority of families with autosomal dominant HPE.
We report 22 patients with normal neuropsychological development and a holoprosencephaly-like (HPE-like) phenotype screened for SHH, SIX3, TGIF, and GLI2.
Genetic testing included chromosomal microarray, Sanger sequencing for SHH, ZIC2, SIX3, and TGIF, and whole-exome sequencing (WES) of 10 trios.ResultsSemilobar HPE was the most common subtype of HPE, seen in 50% of the participants.
To identify whether any mutations of candidate genes including SHH, ZIC2, SIX3, and TGIF exist in a Taiwanese family segregated with holoprosencephaly (HPE) and moyamoya disease.
These YACs narrow the HPE2 critical region to less than 1 Mb and are now being further analyzed to identify the gene causing holoprosencephaly on chromosome 2.
Genomic GLI2 aberrations that mainly result in truncated proteins have been reported to cause holoprosencephaly or holoprosencephaly-like features, sometimes associated with hypopituitarism.
These clinical, biochemical, and molecular studies suggest that HPE and other malformations in SLOS may be caused by incomplete or abnormal modification of the sonic hedgehog protein and, possible, other patterning proteins of the hedgehog class, a hypothesis testable in somatic cell systems.
Heterozygous nonsense and missense mutations of the human TGIF gene have been associated with holoprosencephaly, the most common congenital malformation of the forebrain.
We present the description of a family simultaneously segregating two novel variants in the HPE-associated genes, ZIC2 and GLI2, as well as the results of extensive population-based studies of the variant region in GLI2.