Mice Lacking the Nuclear Pore Complex Protein ALADIN Show Female Infertility but Fail To Develop a Phenotype Resembling Human Triple A Syndrome

Huebner, Angela; Mann, Philipp; Rohde, E; Kaindl, Angela M.; Witt, Martin; Verkade, Paul; Jakubiczka, Sibylle; Menschikowski, Mario; Stoltenburg‐Didinger, Gisela; Koehler, Katrin

doi:10.1128/mcb.26.5.1879-1887.2006

Cited by 41 publications

(33 citation statements)

References 26 publications

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“…This pattern of expression confirms the role of ALADIN in adrenal and CNS function and agrees with the clinical features of triple A syndrome. However, the wide variety and severity of clinical findings in triple A syndrome (1) and the absence of phenotype resembling human disease in AaasK/K mice, indicates that additional factors may be involved in the pathogenesis of this disease (42). Molecular analysis of DNA from patients 4 and 5 did not show mutation in MC2R, MRAP, and AAAS genes.…”

Section: Discussionmentioning

confidence: 97%

“…The majority of mutations in AAAS gene are nonsense, frameshift, or splice site with some missense mutations (23,41). Though the function of ALADIN is not yet well established, this protein localizes in the nuclear pore and is involved in the nucleocytoplasmic transport (17,18,42). Studying natural variants described in triple A syndrome, a mislocalization of mutant ALADIN proteins in the cytoplasm was demonstrated (17,42).…”

Section: Discussionmentioning

confidence: 99%

“…Though the function of ALADIN is not yet well established, this protein localizes in the nuclear pore and is involved in the nucleocytoplasmic transport (17,18,42). Studying natural variants described in triple A syndrome, a mislocalization of mutant ALADIN proteins in the cytoplasm was demonstrated (17,42). Storr et al (43) showed high expression of AAAS mRNA in the adrenal cortex and central nervous system (CNS), mostly in the cerebral cortex, cerebellum, hippocampus, motor-associated nuclei of the brainstem including cranial nerve nuclei, and ventral horn of the spinal cord.…”

Section: Discussionmentioning

confidence: 99%

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Heterogeneity in the molecular basis of ACTH resistance syndrome.

Collares

Antunes‐Rodrigues²,

Moreira³

et al. 2008

European Journal of Endocrinology

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Objective: ACTH resistance syndromes are rare, autosomal, and genetically heterogeneous diseases that include familial glucocorticoid deficiency (FGD) and triple A syndrome. FGD has been shown to segregate with mutations in the gene coding for ACTH receptor (MC2R) or melanocortin 2 receptor accessory protein (MRAP), whereas mutations in the triple A syndrome (AAAS, Allgrove syndrome) gene have been found in segregation with triple A syndrome. We describe the clinical findings and molecular analysis of MC2R, MRAP, and AAAS genes in five Brazilian patients with ACTH resistance syndrome. Design and methods: Genomic DNA from patients and their unaffected relatives was extracted from peripheral blood leucocytes and amplified by PCR, followed by automated sequencing. Functional analysis was carried out using Y6 cells expressing wild-type and mutant MC2R. Results: All five patients showed low cortisol and elevated plasma ACTH levels. One patient had achalasia and alacrima, besides the symptoms of adrenal insufficiency. The molecular analysis of FGD patients revealed a novel p.Gly116Val mutation in the MC2R gene in one patient and p.Met1Ile mutation in the MRAP gene in another patient. Expression of p.Gly116Val MC2R mutant in Y6 cells revealed that this variant failed to stimulate cAMP production. The analysis of the AAAS gene in the patient with triple A syndrome showed a novel g.782_783delTG deletion. The molecular analysis of DNA from other two patients showed no mutation in MC2R, MRAP, or AAAS gene. Conclusions: In conclusion, the molecular basis of ACTH resistance syndrome is heterogeneous, segregating with genes coding for proteins involved with ACTH receptor signaling/expression or adrenal gland development and other unknown genes.European Journal of Endocrinology 159 61-68

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Heterogeneity in the molecular basis of ACTH resistance syndrome.

Collares

Antunes‐Rodrigues²,

Moreira³

et al. 2008

European Journal of Endocrinology

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“…Although the function of ALADIN remains unknown, a human disease called triple-A syndrome is associated with several deletions and point mutations in this protein (Tullio-Pelet et al, 2000). However, since an ALADIN knockout produced a different phenotype in mice (Huebner et al, 2006), it is possible that the function of ALADIN varies with species. Arabidopsis GFP-tagged ALADIN localized to the nuclear envelope (see Supplemental Figure 1 online) and interacted with other nucleoporins ( Figure 1E; see Supplemental Table 1 online).…”

Section: Structure Of the Npc In Arabidopsismentioning

confidence: 99%

Identification and Characterization of Nuclear Pore Complex Components inArabidopsis thaliana

et al. 2010

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The nuclear pore complex (NPC) facilitates nucleocytoplasmic transport, a crucial process for various cellular activities.The NPC comprises ;30 nucleoporins and is well characterized in vertebrates and yeast. However, only eight plant nucleoporins have been identified, and little information is available about the complete molecular structure of plant NPCs. In this study, an interactive proteomic approach was used to identify Arabidopsis thaliana nucleoporins. A series of five cycles of interactive proteomic analysis was performed using green fluorescent protein (GFP)-tagged nucleoporins. The identified nucleoporins were then cloned and subcellular localization analyses were performed. We found that the plant NPC contains at least 30 nucleoporins, 22 of which had not been previously annotated. Surprisingly, plant nucleoporins shared a similar domain organization to their vertebrate (human) and yeast (Saccharomyces cerevisiae) counterparts. Moreover, the plant nucleoporins exhibited higher sequence homology to vertebrate nucleoporins than to yeast nucleoporins. Plant NPCs lacked seven components (NUCLEOPORIN358 [Nup358], Nup188, Nup153, Nup45, Nup37, NUCLEAR DIVISION CYCLE1, and PORE MEMBRANE PROTEIN OF 121 kD) that were present in vertebrate NPCs. However, plants possessed a nucleoporin, Nup136/Nup1, that contained Phe-Gly repeats, and sequence analysis failed to identify a vertebrate homolog for this protein. Interestingly, Nup136-GFP showed greater mobility on the nuclear envelope than did other nucleoporins, and a Nup136/Nup1 deficiency caused various defects in plant development. These findings provide valuable new information about plant NPC structure and function.

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“…ALA-DIN female homozygous knockout mice (Aaas -/-) are viable but sterile. Histological sections of ovaries from wild-type and ALADINdeficient mice did not show any differences, and follicular development and ovulation appeared to be normal (Huebner et al, 2006). Therefore we decided to analyze whether this infertility could be a consequence of ALADIN having a role in meiosis.…”

Section: Deletion Of Aladin Disturbs Oocyte Maturation In Vitromentioning

confidence: 99%

ALADIN is Required for the Production of Fertile Mouse Oocytes

Carvalhal

Stevense

Koehler

et al. 2016

Preprint

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Asymmetric cell divisions depend on the precise placement of the spindle apparatus. In mammalian oocytes, spindles assemble close to the cell's center, but chromosome segregation takes place at the cell periphery where half of the chromosomes are expelled into small, nondeveloping polar bodies at anaphase. By dividing so asymmetrically, most of the cytoplasmic content within the oocyte is preserved, which is critical for successful fertilization and early development. Recently we determined that the nucleoporin ALADIN participates in spindle assembly in somatic cells, and we have also shown that female mice homozygously null for ALADIN are sterile. In this study we show that this protein is involved in specific meiotic stages, including meiotic resumption, spindle assembly, and spindle positioning. In the absence of ALADIN, polar body extrusion is compromised due to problems in spindle orientation and anchoring at the first meiotic anaphase. ALADIN null oocytes that mature far enough to be fertilized in vitro are unable to support embryonic development beyond the two-cell stage. Overall, we find that ALADIN is critical for oocyte maturation and appears to be far more essential for this process than for somatic cell divisions.

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Mice Lacking the Nuclear Pore Complex Protein ALADIN Show Female Infertility but Fail To Develop a Phenotype Resembling Human Triple A Syndrome

Cited by 41 publications

References 26 publications

Heterogeneity in the molecular basis of ACTH resistance syndrome.

Heterogeneity in the molecular basis of ACTH resistance syndrome.

Identification and Characterization of Nuclear Pore Complex Components inArabidopsis thaliana

ALADIN is Required for the Production of Fertile Mouse Oocytes

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