title: 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 deficiency. Three pre-pubertal males (A, B and C) with MGS and short stature due to growth hormone deficiency, 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 identified 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.
authors.affiliation: Department of Pediatrics, University of Campinas, SP, Brazil. gilguer@fcm.unicamp.br
authors.forename: Gil
authors.initials: G
authors.lastname: Guerra-Junior
authors.forename: Angela Maria
authors.initials: AM
authors.lastname: Spinola-Castro
authors.forename: Adriana A
authors.initials: AA
authors.lastname: Siviero-Miachon
authors.forename: Roberto Gomes
authors.initials: RG
authors.lastname: Nogueira
authors.forename: Sofia Helena V
authors.initials: SH
authors.lastname: Lemos-Marini
authors.forename: Lilia Freire Rodrigues
authors.initials: LF
authors.lastname: D'Souza-Li
authors.forename: Priscila Cristina da
authors.initials: PC
authors.lastname: Silva
authors.forename: Emerson Salvador S
authors.initials: ES
authors.lastname: França
authors.forename: Fernanda Caroline
authors.initials: FC
authors.lastname: Soardi
authors.forename: Maricilda Palandi de
authors.initials: MP
authors.lastname: Mello
mesh_terms: D001483:Base Sequence; D002648:Child; D004677:Encephalocele / Q000175:diagnosis; D005136:Eye Proteins / Q000235:genetics*; D006579:Heterozygote; D018398:Homeodomain Proteins / Q000235:genetics*; D019382:Human Growth Hormone / Q000172:deficiency* / Q000627:therapeutic use; D006801:Humans; D007438:Introns / Q000235:genetics; D009154:Mutation; D009898:Optic Disk / Q000002:abnormalities*; D009901:Optic Nerve Diseases / Q000151:congenital / Q000235:genetics*; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors / Q000235:genetics*; D011110:Polymorphism, Genetic; D012097:Repressor Proteins / Q000235:genetics*; D017422:Sequence Analysis, DNA; D013577:Syndrome
chemical_list: D005136:Eye Proteins; D018398:Homeodomain Proteins; D000071841:PAX6 Transcription Factor; C000605730:PAX6 protein, human; D051761:Paired Box Transcription Factors; D012097:Repressor Proteins; D019382:Human Growth Hormone