Absence of mutations in Pax6 gene in three cases of Morning Glory syndrome associated with isolated growth hormone deficiency

Abstract

Morning glory syndrome (MGS) is a congenital optic disc dysplasia often associated with craniofacial anomalies, especially basal encephalocele and hypopituitarism. Clinical signs are varied and often occult. The PAX6 gene is involved in ocular morphogenesis and is expressed in numerous ocular tissues during development especially in the developing central nervous system. The aim of the present study is to evaluate PAX6 in MGS associated with isolated growth hormone defi ciency. Three pre-pubertal males (A, B and C) with MGS and short stature due to growth hormone defi ciency, treated with recombinant human growth hormone with limited response, were reported. Two of them had basal encephalocele. Coding and non-coding sequences corresponding of PAX6 different transcripts were analyzed by direct sequencing. Nucleotide variations causing putative aminoacid change were not observed. Patient A presented the new IVS2+9G>A transition, whereas patients A and C were heterozygous for known single nucleotide polymorphisms (SNP) within the intron 4. In addition, two SNP heterozygoses were observed for patient C in both intron 9 and 13. Sequencing also revealed several nucleotide variations in patient B. Two heterozygoses for known polymorphisms were identifi ed along with a novel C>A nucleotide change in intron 4. This patient also presented a low number on the TG repeat in intron 9 and a new IVS11+33A>T transversion. Gene regulation and transcription of PAX6 are complex processes; there are two major protein isoforms, PAX6(-5a) and PAX6(+5a), and nine transcripts described. Furthermore, extra transcription regulatory elements have been postulated within PAX6 introns. Considering that neither population distributions on PAX6 polymorphism nor their linkeages with diseases have been reported, a functional effect due to alterations described here cannot be discarded.

STAT6, PBX2, and PBRM1 Emerge as Predicted Regulators of 452 Differentially Expressed Genes Associated With Puberty in Brahman Heifers

“…The PAX6 promoter is known as a TF involved in embryonic development and neurulation ( Callaerts et al, 1997 ). A PAX6 mutation was associated with isolated GH deficiency ( Guerra-Junior et al, 2008 ). BHLHE22 has been described as a transcriptional repressor of insulin expression in pancreatic β cells ( Peyton et al, 1996 ; Melkman-Zehavi et al, 2011 ).…”

Internal carotid artery origin of the anterior cerebral artery: A rare anatomic intracranial arterial variation in a child with morning glory disc anomaly and moyamoya vascular pattern; case report and review of literature

“…Some studies have shown sporadic cases with PAX6 mutations, while others failed to demonstrate such relation. [ 6 ] Furthermore, it has been suggested that PAX2 mutations have been associated with MGDA as well. [ 7 ]…”

Unilateral morning glory optic disc anomaly in a case with Down syndrome

“…Mutations in gene PAX6 had been associated with MGS [32,33]. Midline craniofacial defects [13], CHARGE syndrome [34], 47XYY syndrome [35], and neurofibromatosis type 2 [36] have been also reported in association with MGS.…”