scholarly journals Heterozygous defects in PAX6 gene and congenital hypopituitarism

2015 ◽  
Vol 172 (1) ◽  
pp. 37-45 ◽  
Author(s):  
Masaki Takagi ◽  
Keisuke Nagasaki ◽  
Ikuma Fujiwara ◽  
Tomohiro Ishii ◽  
Naoko Amano ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
De Novo ◽  
Chromosomal Rearrangements ◽  
Copy Number Variations ◽  
Hormone Deficiency ◽  
Comparative Genomic ◽  
Pituitary Hormone ◽  
Pax6 Gene ◽  
Pituitary Development ◽  
Congenital Hypopituitarism

BackgroundThe 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.ObjectiveTo identify the role of copy number variations (CNVs) in the etiology of CH and to identify novel genes implicated in CH.Subjects and methodsWe 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.ResultsWe 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.ConclusionsThis 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.

scholarly journals Candidate genes for panhypopituitarism identified by gene expression profiling

2011 ◽  
Vol 43 (19) ◽  
pp. 1105-1116 ◽  
Author(s):  
Amanda H. Mortensen ◽  
James W. MacDonald ◽  
Debashis Ghosh ◽  
Sally A. Camper
Keyword(s):  
Gene Expression ◽  
Molecular Mechanisms ◽  
Regulation Of Gene Expression ◽  
Hormone Deficiency ◽  
Pituitary Hormone ◽  
Human Pituitary ◽  
Temporal Regulation ◽  
Pituitary Development ◽  
Expression Of Genes ◽  
Elevated Expression

Mutations in the transcription factors PROP1 and PIT1 (POU1F1) lead to pituitary hormone deficiency and hypopituitarism in mice and humans. The dysmorphology of developing Prop1 mutant pituitaries readily distinguishes them from those of Pit1 mutants and normal mice. This and other features suggest that Prop1 controls the expression of genes besides Pit1 that are important for pituitary cell migration, survival, and differentiation. To identify genes involved in these processes we used microarray analysis of gene expression to compare pituitary RNA from newborn Prop1 and Pit1 mutants and wild-type littermates. Significant differences in gene expression were noted between each mutant and their normal littermates, as well as between Prop1 and Pit1 mutants. Otx2, a gene critical for normal eye and pituitary development in humans and mice, exhibited elevated expression specifically in Prop1 mutant pituitaries. We report the spatial and temporal regulation of Otx2 in normal mice and Prop1 mutants, and the results suggest Otx2 could influence pituitary development by affecting signaling from the ventral diencephalon and regulation of gene expression in Rathke's pouch. The discovery that Otx2 expression is affected by Prop1 deficiency provides support for our hypothesis that identifying molecular differences in mutants will contribute to understanding the molecular mechanisms that control pituitary organogenesis and lead to human pituitary disease.

A mutation of the β-domain in POU1F1 causes pituitary deficiency due to dominant PIT-1β expression

2021 ◽  
Author(s):  
Shigeru Suzuki ◽  
Kumihiro Matsuo ◽  
Yoshiya Ito ◽  
Atsushi Kobayashi ◽  
Takahide Kokumai ◽  
...  
Keyword(s):  
Hormone Deficiency ◽  
Luciferase Reporter ◽  
Heterozygous Mutation ◽  
Pituitary Hormone ◽  
Pituitary Cells ◽  
Transactivation Domain ◽  
Exon 2 ◽  
Pituitary Development ◽  
Long Term Follow Up ◽  
Alternatively Spliced

Background: POU1F1 encodes both PIT-1α, which plays pivotal roles in pituitary development and GH, PRL and TSHB expression, and the alternatively spliced isoform PIT-1β, which contains an insertion of 26-amino acids (β-domain) in the transactivation domain of PIT-1α due to the use of an alternative splice acceptor at the end of the first intron. PIT-1β is expressed at much lower levels than PIT-1α and represses endogenous PIT-1α transcriptional activity. Although POU1F1 mutations lead to combined pituitary hormone deficiency (CPHD), no patients with β-domain mutations have been reported. Results: Here, we report that a three-generation family exhibited different degrees of CPHD, including growth hormone deficiency with intrafamilial variability of prolactin/TSH insufficiency and unexpected prolactinoma occurrence. The CPHD was due to a novel POU1F1 heterozygous variant (c.143-69T>G) in intron 1 of PIT-1α (RefSeq number NM_000306) or as c.152T>G (p.Ile51Ser) in exon 2 of PIT-1β (NM_001122757). Gene splicing experiments showed that this mutation yielded the PIT-1β transcript without other transcripts. Lymphocyte PIT-1β mRNA expression was significantly higher in the patients with the heterozygous mutation than a control. A luciferase reporter assay revealed that the PIT-1β-Ile51Ser mutant repressed PIT-1α and abolished transactivation capacity for the rat prolactin promoter in GH3 pituitary cells. Conclusions: We describe, for the first time, that PIT-1β mutation can cause CPHD through a novel genetic mechanism, such as PIT-1β overexpression, and that POU1F1 mutation might be associated with a prolactinoma. Analysis of new patients and long-term follow-up are needed to clarify the characteristics of PIT-1β mutations.

Lhx4 and Prop1 are required for cell survival and expansion of the pituitary primordia

Development ◽  
2002 ◽  
Vol 129 (18) ◽  
pp. 4229-4239 ◽  
Author(s):  
Lori T. Raetzman ◽  
Robert Ward ◽  
Sally A. Camper
Keyword(s):  
Cell Survival ◽  
Anterior Pituitary ◽  
Molecular Genetic ◽  
Cell Types ◽  
Hormone Deficiency ◽  
Pituitary Hormone ◽  
Pituitary Cells ◽  
Temporal Shift ◽  
Pituitary Development ◽  
Show Evidence

Deficiencies in the homeobox transcription factors LHX4 and PROP1 cause pituitary hormone deficiency in both humans and mice. Lhx4 and Prop1 mutants exhibit severe anterior pituitary hypoplasia resulting from limited differentiation and expansion of most specialized cell types. Little is known about the mechanism through which these genes promote pituitary development. In this study we determined that the hypoplasia in Lhx4 mutants results from increased cell death and that the reduced differentiation is attributable to a temporal shift in Lhx3 activation. In contrast, Prop1 mutants exhibit normal cell proliferation and cell survival but show evidence of defective dorsal-ventral patterning. Molecular genetic analyses reveal that Lhx4 and Prop1 have overlapping functions in early pituitary development. Double mutants exhibit delayed corticotrope specification and complete failure of all other anterior pituitary cell types to differentiate. Thus, Lhx4 and Prop1 have critical, but mechanistically different roles in specification and expansion of specialized anterior pituitary cells.

scholarly journals Clinical Report of a 17q12 Microdeletion with Additionally Unreported Clinical Features

2014 ◽  
Vol 2014 ◽  
pp. 1-6 ◽  
Author(s):  
Jennifer L. Roberts ◽  
Stephanie K. Gandomi ◽  
Melissa Parra ◽  
Ira Lu ◽  
Chia-Ling Gau ◽  
...  
Keyword(s):  
De Novo ◽  
Abdominal Ultrasound ◽  
Autism Spectrum ◽  
Copy Number Variations ◽  
Comparative Genomic ◽  
Clinical Report ◽  
Snp Analysis ◽  
New Genotype ◽  
Compulsive Behaviors ◽  
Oppositional Defiance

Copy number variations involving the 17q12 region have been associated with developmental and speech delay, autism, aggression, self-injury, biting and hitting, oppositional defiance, inappropriate language, and auditory hallucinations. We present a tall-appearing 17-year-old boy with marfanoid habitus, hypermobile joints, mild scoliosis, pectus deformity, widely spaced nipples, pes cavus, autism spectrum disorder, intellectual disability, and psychiatric manifestations including physical and verbal aggression, obsessive-compulsive behaviors, and oppositional defiance. An echocardiogram showed borderline increased aortic root size. An abdominal ultrasound revealed a small pancreas, mild splenomegaly with a 1.3 cm accessory splenule, and normal kidneys and liver. A testing panel for Marfan, aneurysm, and related disorders was negative. Subsequently, a 400 K array-based comparative genomic hybridization (aCGH) + SNP analysis was performed which identified ade novosuspected pathogenic deletion on chromosome 17q12 encompassing 28 genes. Despite the limited number of cases described in the literature with 17q12 rearrangements, our proband’s phenotypic features both overlap and expand on previously reported cases. Since syndrome-specific DNA sequencing studies failed to provide an explanation for this patient’s unusual habitus, we postulate that this case represents an expansion of the 17q12 microdeletion phenotype. Further analysis of the deleted interval is recommended for new genotype-phenotype correlations.

scholarly journals A case of germline mosaicism for a 7q32.1q33 deletion in a sperm donor: consequences on pregnancy follow-up and recommendations

2020 ◽  
Vol 30 (1) ◽  
Author(s):  
Celine Chalas ◽  
Aline Receveur ◽  
Nelly Frydman ◽  
Nathalie Massin ◽  
Gerard Tachdjian ◽  
...  
Keyword(s):  
Chromosomal Rearrangements ◽  
Rare Event ◽  
Copy Number Variations ◽  
Paternal Age ◽  
Comparative Genomic ◽  
Fish Analysis ◽  
Sperm Donor ◽  
Germline Mosaicism ◽  
Talipes Equinovarus

Abstract Background Germline mosaicism is considered to be a rare event. However, its occurrence is underestimated due to the limited availability of germ cells. The genomic variations that underlie this phenomenon comprise single nucleotide polymorphism (SNPs), copy number variations (CNVs) and aneuploidies. In the case of CNVs, deletions are more frequent in the paternal germline while duplications are more commonly maternal in origin. Germline mosaicism increases with paternal age as the risk of SNPs increase with the number of germ cell divisions. We here report a case of germline mosaicism in the spermatozoa of a donor that resulted in one pathological pregnancy. Results Straws from the same sperm donor were provided to seven recipient couples, resulting in four pregnancies. Second trimester ultrasound analysis revealed bilateral talipes equinovarus associated with growth retardation in one of these pregnancies. Array-comparative genomic hybridization (CGH) carried out after amniocentesis revealed a 4 Mb deletion in the 7q32.1q33 region. The blood karyotypes and array-CGHs were normal in the mother, as well as in the donor. However, the microsatellite profile indicated a paternal origin. Fluorescent in situ hybridization (FISH) analysis of the donor’s spermatozoa revealed the same chromosomal rearrangements in 12% of the spermatozoa population. Due to the documented risk of mental retardation associated with genomic rearrangements in the same region, the couple decided to terminate the pregnancy. Amniocentesis was performed in the other couples, which yielded normal FISH analysis results. Conclusions Several cases of germline mosaicism have been reported to date, but their frequency is probably underestimated. Moreover, it is important to note that germline mosaicism cannot be ruled out by conventional cytogenetic screening of blood cells. This case highlights the need for close follow-up of every pregnancy obtained through gamete donation, given that the occurrence of germline mosaicism may have major consequences when multiple pregnancies are obtained concomitantly.

scholarly journals Auxological and endocrine phenotype in a population-based cohort of patients with PROP1 gene defects

2005 ◽  
Vol 153 (3) ◽  
pp. 389-396 ◽  
Author(s):  
Jan Lebl ◽  
Jan Vosáhlo ◽  
Roland W Pfaeffle ◽  
Heike Stobbe ◽  
Jana Černá ◽  
...  
Keyword(s):  
Genomic Analysis ◽  
Population Based ◽  
Hormone Deficiency ◽  
Heterozygous Mutation ◽  
Pituitary Hormone ◽  
Phenotypic Analysis ◽  
Phenotypic Data ◽  
Sibling Pairs ◽  
Pituitary Development ◽  
Gene Defects

Objective: Multiple pituitary hormone deficiency (MPHD) may result from defects of transcription factors that govern early pituitary development. We aimed to establish the prevalence of HESX1, PROP1, and POU1F1 gene defects in a population-based cohort of patients with MPHD and to analyse the phenotype of affected individuals. Design and methods: Genomic analysis was carried out on 74 children and adults with MPHD from the Czech Republic (including four sibling pairs). Phenotypic data were collected from medical records and referring physicians. Results: One patient carried a heterozygous mutation of POU1F1 (71C > T), and 18 patients (including three sibling pairs) had a PROP1 mutation (genotypes 150delA/301delGA/9/, 301delGA/301-delGA/8/, or 301delGA/349T > A/1/). A detailed longitudinal phenotypic analysis was performed for patients with PROP1 mutations (n = 17). The mean ( ±s.d.) birth length SDS of these patients (0.12 ± 0.76) was lower than expected based on their mean ( ±s.d.) birth weight SDS (0.63 ± 1.27; P = 0.01). Parental heights were normal. The patients’ mean ( ±s.d.) height SDS declined to −1.5 ± 0.9, −3.6 ± 1.3 and −4.1 ± 1.2 at 1.5, 3 and 5 years of age, respectively. GH therapy, initiated at 6.8 ± 3.2 years of age (mean dose: 0.022 mg/kg per day), led to substantial growth acceleration in all patients. Mean adult height (n = 7) was normal when adjusted for mid-parental height. ACTH deficiency developed in two out of seven young adult patients. Conclusions: PROP1 defects are a prevalent cause of MPHD. We suggest that testing for PROP1 mutations in patients with MPHD might become standard practice in order to predict risk of additional pituitary hormone deficiencies.

scholarly journals Increased Frequency of Copy Number Variations Revealed by Array Comparative Genomic Hybridization in the Offspring of Male Mice Exposed to Low Dose-Rate Ionizing Radiation

2021 ◽  
Vol 22 (22) ◽  
pp. 12437
Author(s):  
Keiji Ogura ◽  
Yoshiko Ayabe ◽  
Chihiro Harada ◽  
Ignacia Braga Tanaka ◽  
Satoshi Tanaka ◽  
...  
Keyword(s):  
Ionizing Radiation ◽  
Dose Rate ◽  
Copy Number ◽  
Array Comparative Genomic Hybridization ◽  
Low Dose ◽  
De Novo ◽  
Copy Number Variations ◽  
Comparative Genomic ◽  
Male Mice ◽  
Low Dose Rate

There is very little information on the transgenerational or genetic effects of low dose-rate ionizing radiation. We report the detection of the transgenerational effects of chronic low dose-rate irradiation in mice, at the molecular level in the whole genome, using array comparative genomic hybridization technology. We observed that the number of the mice with de novo copy number variations (specifically, deletions) was significantly increased in the offspring of C57BL/6J male mice exposed to 20 mGy/day gamma-rays for 400 days (total dose: 8000 mGy), as compared to non-irradiated controls. We did not detect any difference in the size of the de novo deletions between the irradiated and the non-irradiated groups. An analysis of the life span of the offspring suggested a possibility that de novo copy-number variations may be associated with shorter life spans.

Aetiology, genes, and environment

ESC CardioMed ◽  
2018 ◽  
pp. 742-746
Author(s):  
Elisavet Fotiou ◽  
Bernard Keavney
Keyword(s):  
De Novo ◽  
Chromosomal Rearrangements ◽  
Recurrence Risk ◽  
Copy Number Variations ◽  
Deletion Syndrome ◽  
Clinical Genetics ◽  
Single Nucleotide ◽  
Neurodevelopmental Delay ◽  
Substantial Progress ◽  
Neurodevelopmental Abnormalities

Genetic factors predisposing to congenital heart disease (CHD) are characterized by extreme heterogeneity, comprising changes to the genome at all levels of variation from chromosomal aneuploidy to single nucleotide mutations. About 15–20% of patients with CHD have underlying genetic causes identifiable by currently standard clinical genetics laboratory testing, including patients with Down syndrome, Turner syndrome, 22q11 deletion syndrome, other chromosomal rearrangements, and multisystem conditions mediated by single nucleotide changes in particular genes (e.g. Noonan’s syndrome). Extracardiac malformations and/or neurodevelopmental abnormalities characteristic of these conditions are important diagnostic cues. Mendelian families with isolated non-syndromic CHD are very rare. In the remaining 80% of cases, CHD is apparently ‘sporadic’ and the empirical recurrence risk to a sibling of an index case in such families is approximately 3%. This low recurrence risk suggests that de novo events, that is, new mutations in affected offspring absent in the parents, are an important potential genetic cause of CHD. De novo copy number variations such as 1q21.1 duplication have been shown to contribute to aetiology in 5–10% of apparently sporadic patients. Recent studies have also shown that approximately 20% of patients without recognized syndromic presentations, but with CHD accompanied by extracardiac malformations and/or neurodevelopmental delay, may have pathogenic de novo single nucleotide changes discoverable by exome sequencing. Continuing advances in genomic technologies present the prospect of substantial progress in the understanding of the genetic predisposition to CHD, but further research in large cohort studies is required.

scholarly journals SAT-291 SIX3 Is Essential for Hypothalamic and Pituitary Development

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Hironori Bando ◽  
Michelle L Brinkmeier ◽  
Frederic Castinetti ◽  
Peter Gergics ◽  
Amanda H Mortensen ◽  
...  
Keyword(s):  
Bmp Signaling ◽  
Pituitary Hormone ◽  
Homeodomain Protein ◽  
Loss Of Function ◽  
Shh Signaling ◽  
Rathke’S Pouch ◽  
Pituitary Development ◽  
Rathke's Pouch ◽  
Oral Ectoderm ◽  
Congenital Hypopituitarism

Abstract The genetic basis for congenital hypopituitarism and related disorders is beginning to emerge, and over causal 30 genes have been identified, including six in the SHH signaling pathway. Mutations in some of these genes can also cause holoprosencephaly (HPE) or septo-optic dysplasia. SIX3 is a homeodomain protein expressed in the developing brain, pituitary gland, and eye. It activates SHH signaling and represses BMP signaling. Heterozygous mutations in SIX3 cause variable HPE in humans and mice. We identified a rare, heterozygous variant in SIX3 in two children with neonatal GH and TSH deficiency and stalk interruption, p.P74R. Using transient transfection in 3T3 cells, we demonstrated that the variant reduced the ability of SIX3 to transactivate the SHH enhancer and promoter of FOXG1, suggesting that the variant could be deleterious. To understand the role of SIX3 in hypothalamic and pituitary development we used Nkx2.1-cre and Prop1-cre to delete Six3 in mice. The Nkx2.1-cre, Six3flox/flox embryos had no evidence of infundibulum evagination or expression of Fgf10 or Tcf7l2 at e11.5. The oral ectoderm invaginated in mutants, but no definitive Rathke’s pouch formed. There was no evidence of Lhx3 expression and only trace amounts of Pitx1, indicating that pituitary induction failed due to the lack of Six3 in the developing hypothalamus. Similarly, disruption of Six3 expression in Rathke’s pouch using Prop1-cre ablated pituitary development. Together, these data reveal essential roles of Six3 in both the neural and oral ectoderm for hypothalamic and pituitary development, respectively. Heterozygous loss of function variants in SIX3 could be a contributor to multiple pituitary hormone deficiencies in children, especially if there are associated craniofacial abnormalities.

scholarly journals Pan-genome analyses of peach and its wild relatives provide insights into the genetics of disease resistance and species adaptation

2020 ◽  
Author(s):  
Ke Cao ◽  
Zhen Peng ◽  
Xing Zhao ◽  
Yong Li ◽  
Kuozhan Liu ◽  
...  
Keyword(s):  
High Altitude ◽  
Molecular Mechanisms ◽  
De Novo ◽  
Genomic Analysis ◽  
Gene Families ◽  
Wild Relatives ◽  
Comparative Genomic ◽  
High Altitude Adaptation ◽  
Pan Genome ◽  
Altitude Adaptation

AbstractAs a foundation to understand the molecular mechanisms of peach evolution and high-altitude adaptation, we performed de novo genome assembling of four wild relatives of P. persica, P. mira, P. kansuensis, P. davidiana and P. ferganensis. Through comparative genomic analysis, abundant genetic variations were identified in four wild species when compared to P. persica. Among them, a deletion, located at the promoter of Prupe.2G053600 in P. kansuensis, was validated to regulate the resistance to nematode. Next, a pan-genome was constructed which comprised 15,216 core gene families among four wild peaches and P. perisca. We identified the expanded and contracted gene families in different species and investigated their roles during peach evolution. Our results indicated that P. mira was the primitive ancestor of cultivated peach, and peach evolution was non-linear and a cross event might have occurred between P. mira and P. dulcis during the process. Combined with the selective sweeps identified using accessions of P. mira originating from different altitude regions, we proposed that nitrogen recovery was essential for high-altitude adaptation of P. mira through increasing its resistance to low temperature. The pan-genome constructed in our study provides a valuable resource for developing elite cultivars, studying the peach evolution, and characterizing the high-altitude adaptation in perennial crops.

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