A novel de novo frameshift mutation in NR0B1 and low prenatal estriol in adrenal hypoplasia congenita

2018 ◽  
Vol 1433 (1) ◽  
pp. 7-11 ◽  
Author(s):  
Ahmed Khattab ◽  
Carol Nelson-Williams ◽  
Vivienne Cabreza ◽  
Anne Macdonald ◽  
Erin Loring ◽  
...  
Keyword(s):  
Frameshift Mutation ◽  
De Novo ◽  
Adrenal Hypoplasia Congenita ◽  
Adrenal Hypoplasia

scholarly journals Three Novel Mutations and a De Novo Deletion Mutation of the DAX-1 Gene in Patients with X-Linked Adrenal Hypoplasia Congenita

1997 ◽  
Vol 82 (11) ◽  
pp. 3835-3841 ◽  
Author(s):  
Jun Nakae ◽  
Shuji Abe ◽  
Toshihiro Tajima ◽  
Nozomi Shinohara ◽  
Mari Murashita ◽  
...  
Keyword(s):  
Missense Mutation ◽  
Frameshift Mutation ◽  
De Novo ◽  
Stop Codon ◽  
Premature Stop Codon ◽  
Deletion Mutation ◽  
Orphan Nuclear Receptor ◽  
Missense Mutations ◽  
Adrenal Hypoplasia Congenita ◽  
Adrenal Hypoplasia

The DAX-1 [DSS (dosage sensitive sex)-AHC critical region on the X, gene 1] gene is responsible for X-linked adrenal hypoplasia congenita (AHC). However, DAX-1 protein structure-function relationships are not well understood. Identification of missense mutations may help to reveal these relationships. We analyzed the DAX-1 gene from seven patients in six kindreds with X-linked AHC and identified one frameshift mutation, two missense mutations, and three deletion mutations. Case 1 had a 388delAG frameshift mutation, inducing a premature stop codon at position 70. Case 2 had a missense mutation, Lys382Asn, which encodes an asparagine (Asn) for lysine (Lys) at position 382. Sibling cases of 3-1 and 3-2 had a missense mutation of Trp291Cys, which encodes a substitution of cysteine (Cys) for tryptophan (Try) at position 291. The tryptophan (Trp) at position 291 and lysine (Lys) at position 382 in human DAX-1 protein are highly conserved among other related orphan nuclear receptor superfamily members. Cases 4, 5, and 6 showed deletion mutation. In case 6, a de novo deletion mutation was revealed by both southern hybridization and polymerase chain reaction (PCR) of a GGAA tetranucleotide tandem repeat. These findings suggest that: 1) Trp at position 291 and Lys at position 382, located in the C-terminal presumptive ligand binding domain, are important to the functional role of the DAX-1 protein in adrenal embryogenesis and/or in hypothalamic-pituitary activity; and 2) molecular analysis of the DAX-1 gene may help genetic counseling, even in cases with deletion mutation, because a detection of de novo deletion may exclude another affected or carrier child.

Novel Mutations in DAX1 of X-Linked Adrenal Hypoplasia Congenita Over Several Generations in One Family

2013 ◽  
Vol 19 (4) ◽  
pp. e105-e111 ◽  
Author(s):  
Xu Xiao-qin ◽  
Feng Yue-ying ◽  
Yuan Wen-xia ◽  
Huang Ke ◽  
Liang Li ◽  
...  
Keyword(s):  
Novel Mutations ◽  
Adrenal Hypoplasia Congenita ◽  
Adrenal Hypoplasia

Delayed diagnosis of adrenal hypoplasia congenita in two adult brothers

1995 ◽  
Vol 28 (3) ◽  
pp. 333
Author(s):  
V. Chetty ◽  
J.D. Booth ◽  
E. Dunn ◽  
S. Hill ◽  
G. Luxton
Keyword(s):  
Delayed Diagnosis ◽  
Adrenal Hypoplasia Congenita ◽  
Adrenal Hypoplasia

scholarly journals A disease-associated frameshift mutation in caveolin-1 disrupts caveolae formation and function through introduction of a de novo ER retention signal

2017 ◽  
Vol 28 (22) ◽  
pp. 3095-3111 ◽  
Author(s):  
Courtney A. Copeland ◽  
Bing Han ◽  
Ajit Tiwari ◽  
Eric D. Austin ◽  
James E. Loyd ◽  
...  
Keyword(s):  
Frameshift Mutation ◽  
De Novo ◽  
Dominant Negative ◽  
Caveolin 1 ◽  
Protein Levels ◽  
C Terminus ◽  
Er Retention ◽  
And Function ◽  
Er Retention Signal ◽  
Retention Signal

Caveolin-1 (CAV1) is an essential component of caveolae and is implicated in numerous physiological processes. Recent studies have identified heterozygous mutations in the CAV1 gene in patients with pulmonary arterial hypertension (PAH), but the mechanisms by which these mutations impact caveolae assembly and contribute to disease remain unclear. To address this question, we examined the consequences of a familial PAH-associated frameshift mutation in CAV1, P158PfsX22, on caveolae assembly and function. We show that C-terminus of the CAV1 P158 protein contains a functional ER-retention signal that inhibits ER exit and caveolae formation and accelerates CAV1 turnover in Cav1–/– MEFs. Moreover, when coexpressed with wild-type (WT) CAV1 in Cav1–/– MEFs, CAV1-P158 functions as a dominant negative by partially disrupting WT CAV1 trafficking. In patient skin fibroblasts, CAV1 and caveolar accessory protein levels are reduced, fewer caveolae are observed, and CAV1 complexes exhibit biochemical abnormalities. Patient fibroblasts also exhibit decreased resistance to a hypo-osmotic challenge, suggesting the function of caveolae as membrane reservoir is compromised. We conclude that the P158PfsX22 frameshift introduces a gain of function that gives rise to a dominant negative form of CAV1, defining a new mechanism by which disease-associated mutations in CAV1 impair caveolae assembly.

scholarly journals De novo frameshift mutation inCOUP-TFII(NR2F2) in human congenital diaphragmatic hernia

2016 ◽  
Vol 170 (9) ◽  
pp. 2457-2461 ◽  
Author(s):  
Frances A. High ◽  
Pooja Bhayani ◽  
Jay M. Wilson ◽  
Carol J. Bult ◽  
Patricia K. Donahoe ◽  
...  
Keyword(s):  
Congenital Diaphragmatic Hernia ◽  
Diaphragmatic Hernia ◽  
Frameshift Mutation ◽  
De Novo

scholarly journals A novel DAX1/NR0B1 mutation in a patient with adrenal hypoplasia congenita and hypogonadotropic hypogonadism

2012 ◽  
Vol 56 (8) ◽  
pp. 496-500 ◽  
Author(s):  
Claudilene Battistin ◽  
Hamilton Cabral de Menezes Filho ◽  
Sorahia Domenice ◽  
Mirian Yumie Nishi ◽  
Thais Della Manna ◽  
...  
Keyword(s):  
Novel Mutation ◽  
Hypogonadotropic Hypogonadism ◽  
Failure To Thrive ◽  
The Novel ◽  
Site Analysis ◽  
Adrenal Hypoplasia Congenita ◽  
Normal Individuals ◽  
Exon 1 ◽  
Adrenal Hypoplasia ◽  
Low Levels

We report a case of adrenal hypoplasia congenita (AHC) and hypogonadotropic hypogonadism (HH) due to a novel DAX1 mutation. A 19-month-old boy with hyperpigmentation and failure to thrive came to our service for investigation. Three brothers of the patient had died due to adrenal failure, and a maternal cousin had adrenal insufficiency. Adrenoleukodystrophy was excluded. MRI showed normal pituitary and hypothalamus. Plasma hormone evaluation revealed high ACTH (up to 2,790 pg/mL), and low levels of androstenedione, DHEA-S, 11-deoxycortisol, and cortisol. At 14 years of age the patient was still prepubescent, his weight was 43.6 kg (SDS: -0.87) and his height was 161 cm (SDS: -0.36), with normal body proportions. In the GnRH test, basal and maximum values of LH and FSH were respectively 0.6/2.1 and < 1.0/< 1.0 U/L. Molecular investigation identified a novel mutation that consists of a deletion of codon 372 (AAC; asparagine) in exon 1 of DAX1. This mutation was not found in a study of 200 alleles from normal individuals. Prediction site analysis indicated that this alteration, located in the DAX1 ligand-binding domain, may damage DAX1 protein. We hypothesize that the novel (p.Asp372del) DAX1 mutation might be able to cause a disruption of DAX1 function, and is probably involved in the development of AHC and HH in this patient. Arq Bras Endocrinol Metab. 2012;56(8):496-500

scholarly journals Identification and Functional Characterization of a Novel De Novo RUNX2 Frameshift Mutation Associated With Cleidocranial Dysplasia

2021 ◽  
Author(s):  
Lei Gong ◽  
Bekzod Odilov ◽  
Feng Han ◽  
Fuqiang Liu ◽  
Yujing Sun ◽  
...  
Keyword(s):  
Frameshift Mutation ◽  
De Novo ◽  
Novel Mutation ◽  
Genetic Disorder ◽  
Functional Characterization ◽  
Sporadic Case ◽  
Luciferase Assay ◽  
Cleidocranial Dysplasia ◽  
Wild Type ◽  
Bone And Cartilage Development

Abstract BackgroundCleidocranial dysplasia (CCD) is a rare genetic disorder affecting bone and cartilage development. Clinical features of CCD comprise short stature, delayed ossification of craniofacial structures with numerous Wormian bones, underdeveloped or aplastic clavicles and multiple dental anomalies. Several studies have revealed that CCD development is strongly linked with different mutations in Runt-related Transcription Factor 2 (RUNX2) gene. In this study, we report a case with typical CCD presentations. MethodsWe performed genetic testing of participants and found a novel RUNX2 frameshift mutation: c.1550delT in a sporadic case. We also compared the functional activity of the mutant and wild-type RUNX2 through immunofluorescence microscopy and osteocalcin promoter luciferase assay. ResultsBoth mutant RUNX2 and wild‑type RUNX2 protein were similarly confined in the nuclei. The novel mutation caused abrogative transactivation activity of RUNX2 on osteocalcin promoter. ConclusionsWe explored a novel RUNX2 deletion/frameshift mutation in a sporadic CCD patient. This finding emphasizes on crucial role of VWRPY domain in RUNX2 transactivation ability.

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