Compound heterozygosity for mutations in <i>PAX6</i> in a patient with complex brain anomaly, neonatal diabetes mellitus, and microophthalmia

Solomon, Benjamin D.; Pineda-Álvarez, Daniel E.; Balog, Joan Z.; Hadley, Donald W.; Gropman, Andrea; Nandagopal, R.; Han, Joan C.; Hahn, Jin S.; Blain, Delphine; Brooks, Brian P.; Muenke, Maximilian

doi:10.1002/ajmg.a.33081

Cited by 89 publications

(58 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To date, more than 350 mutations or variants in PAX6 have been reported (12), and almost all were found in the heterozygous state. Although extremely rare, at least four patients harboring biallelic mutations in PAX6 have been reported (13,14,15). Three patients were stillborn or died in early infancy with severe CNS anomalies, but one long surviving patient among them showed MPHD and anterior pituitary hypoplasia (13), further supporting a role for PAX6 in the pituitary development in human.…”

Section: Discussionmentioning

confidence: 99%

Heterozygous defects in PAX6 gene and congenital hypopituitarism

Takagi

Nagasaki

Fujiwara

et al. 2015

European Journal of Endocrinology

View full text Add to dashboard Cite

Background: The prevalence of congenital hypopituitarism (CH) attributable to known transcription factor mutations appears to be rare and other causative genes for CH remain to be identified. Due to the sporadic occurrence of CH, de novo chromosomal rearrangements could be one of the molecular mechanisms participating in its etiology, especially in syndromic cases. Objective: To identify the role of copy number variations (CNVs) in the etiology of CH and to identify novel genes implicated in CH. Subjects and methods: We enrolled 88 (syndromic: 30; non-syndromic: 58) Japanese CH patients. We performed an array comparative genomic hybridization screening in the 30 syndromic CH patients. For all the 88 patients, we analyzed PAX6 by PCR-based sequencing. Results: We identified one heterozygous 310-kb deletion of the PAX6 enhancer region in one patient showing isolated GH deficiency (IGHD), cleft palate, and optic disc cupping. We also identified one heterozygous 6.5-Mb deletion encompassing OTX2 in a patient with bilateral anophthalmia and multiple pituitary hormone deficiency. We identified a novel PAX6 mutation, namely p.N116S in one non-syndromic CH patient showing IGHD. The p.N116S PAX6 was associated with an impairment of the transactivation capacities of the PAX6-binding elements. Conclusions: This study showed that heterozygous PAX6 mutations are associated with CH patients. PAX6 mutations may be associated with diverse clinical features ranging from severely impaired ocular and pituitary development to apparently normal phenotype. Overall, this study identified causative CNVs with a possible role in the etiology of CH in !10% of syndromic CH patients.

show abstract

Section: Discussionmentioning

confidence: 99%

Heterozygous defects in PAX6 gene and congenital hypopituitarism

Takagi

Nagasaki

Fujiwara

et al. 2015

European Journal of Endocrinology

View full text Add to dashboard Cite

show abstract

“…Downstream of NEUROG3, four other transcription factors have been identified as causative for PNDM when mutated: NEUROD1 (Rubio-Cabezas et al, 2010), NKX2.2 , PAX6 (Solomon et al, 2009) and MNX1 (Bonnefond et al, 2013;Flanagan et al, 2014). The first three factors are expressed in human β-cells from early fetal development onwards (Lyttle et al, 2008;Jennings et al, 2013), with NEUROD1 and NKX2.2 considered to be direct targets of NEUROG3 action (Sussel et al, 1998;Gradwohl et al, 2000).…”

Section: Other Causes Of Permanent Neonatal Diabetes Reflecting Abnormentioning

confidence: 99%

Human pancreas development

et al. 2015

View full text Add to dashboard Cite

A wealth of data and comprehensive reviews exist on pancreas development in mammals, primarily mice, and other vertebrates. By contrast, human pancreatic development has been less comprehensively reviewed. Here, we draw together those studies conducted directly in human embryonic and fetal tissue to provide an overview of what is known about human pancreatic development. We discuss the relevance of this work to manufacturing insulin-secreting β-cells from pluripotent stem cells and to different aspects of diabetes, especially permanent neonatal diabetes, and its underlying causes.

show abstract

“…37,38 The third child survived with severe microphthalmia and microcephaly. 39 Chromosomal rearrangements in isolated aniridia and WAGR syndrome Isolated aniridia can also be caused by chromosomal deletions affecting all or part of the PAX6 region, or translocations and inversions that disrupt the transcription unit or control elements. 4,19,25,30 PAX6 is associated with a downstream cluster of highly conserved transcriptional regulatory elements, located in introns of the adjacent ELP4 gene.…”

Section: Central Nervous Systemmentioning

confidence: 99%