A Mutant Mouse with Severe Anemia and Skin Abnormalities Controlled by a New Allele of the Flaky Skin (fsn) Locus

Takabayashi, Shuji; Katoh, Hideki

doi:10.1538/expanim.54.339

Cited by 9 publications

(6 citation statements)

References 13 publications

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“…The flaky skin (fsn) mice showed abnormalities in the immune system such as enlarged peripheral lymph nodes, hyperreactive lymphoid cells, which are quite different from the SCID-like phenotypes observed in human patients. The fsn, int and hea mice all showed papulosquamous skin disorders, and anemia with hematopoietic abnormalities (17)(18)(19), also very different from the phenotypes shown in human mutations. Although few gastrointestinal phenotypes were observed in these mice, fsn mice did show severe weight loss with diarrhea and intestinal apoptosis, (14,20), similar to those seen in the infantile patients reported in Avitzur et al The difference between manifestations in mouse and human might be explained by potential differences in function between the TTC7A orthologs.…”

Section: Discussionmentioning

confidence: 76%

“…Interestingly, VEOIBD is also commonly observed in SCID patients who have atypical manifestations, caused often by hypomorphic mutations in SCID genes (15), suggesting correlation in the development of the two systems. There are three spontaneously arising mutations in the mouse TTC7A ortholog, Ttc7 (17)(18)(19), but little phenotypic similarities were observed between the mouse models and human patients. The flaky skin (fsn) mice showed abnormalities in the immune system such as enlarged peripheral lymph nodes, hyperreactive lymphoid cells, which are quite different from the SCID-like phenotypes observed in human patients.…”

Section: Discussionmentioning

confidence: 99%

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Compound heterozygous mutations in TTC7A cause familial multiple intestinal atresias and severe combined immunodeficiency

et al. 2015

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Familial multiple intestinal atresias is an autosomal recessive disease with or without combined immunodeficiency. In the last year, several reports have described mutations in the gene TTC7A as causal to the disease in different populations. However, exact correlation between different genotypes and various phenotypes are not clear. In this study, we report identification of novel compound heterozygous mutations in TTC7A gene in a Malay girl with familial multiple intestinal atresias and severe combined immunodeficiency (MIA-SCID) by whole exome sequencing. We found two mutations in TTC7A: one that destroyed a putative splicing acceptor at the junction of intron 17/exon 18 and one that introduced a stop codon that would truncate the last two amino acids of the encoded protein. Reviewing the recent reports on TTC7A mutations reveals correlation between the position and nature of the mutations with patient survival and clinical manifestations. Examination of public databases also suggests carrier status for healthy individuals, making a case for population screening on this gene, especially in populations with suspected frequent founder mutations.

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Section: Discussionmentioning

confidence: 76%

Section: Discussionmentioning

confidence: 99%

Compound heterozygous mutations in TTC7A cause familial multiple intestinal atresias and severe combined immunodeficiency

et al. 2015

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“…31 Spontaneous mutations in the murine TTC7A orthologue, Ttc7 , have been identified in the flaky skin ( fsn ) mouse 32–37 , the hereditary erythroblastic anemia ( hea ) mouse 30, 38 , as well as the Ttc7 fsn-Jic mouse. 39, 40 These mouse models show anemia, skin abnormalities, and immune dysregulation, but not intestinal atresia, although forestomach epithelial hyperplasia is present in fsn mice. It is plausible that the actual function of the human TTC7A protein and its murine orthologue Ttc7 may have diversified during evolution, although they share 88% amino acid sequence homology (Fig E8).…”

Section: Discussionmentioning

confidence: 99%

Whole-exome sequencing identifies tetratricopeptide repeat domain 7A ( TTC7A ) mutations for combined immunodeficiency with intestinal atresias

Chen

Giliani

Lanzi

et al. 2013

Journal of Allergy and Clinical Immunology

145

152

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Background Combined Immunodeficiency with Multiple Intestinal Atresias (CID-MIA) is a rare hereditary disease characterized by intestinal obstructions and profound immune defects. Objective We sought to determine the underlying genetic causes of CID-MIA by analyzing the exomic sequence of 5 patients and their healthy direct relatives from 5 unrelated families. Methods We performed whole exome sequencing on 5 CID-MIA patients and 10 healthy direct family members belonging to 5 unrelated families with CID-MIA. We also performed targeted Sanger sequencing for the candidate gene TTC7A on 3 additional CID-MIA patients. Results Through analysis and comparison of the exomic sequence of the individuals from these 5 families, we identified biallelic damaging mutations in the TTC7A gene, for a total of 7 distinct mutations. Targeted TTC7A gene sequencing in 3 additional unrelated patients with CID-MIA revealed biallelic deleterious mutations in two of them, as well as an aberrant splice product in the third patient. Staining of normal thymus showed that the TTC7A protein is expressed in thymic epithelial cells as well as in thymocytes. Moreover, severe lymphoid depletion was observed in the thymus and peripheral lymphoid tissues from two patients with CID-MIA. Conclusions We identified deleterious mutations of the TTC7A gene in 8 unrelated patients with CID-MIA and demonstrated that the TTC7A protein is expressed in the thymus. Our results strongly suggest that TTC7A gene defects cause CID-MIA. Clinical Implications Damaging mutations in the gene TTC7A should be scrutinized in patients with CID-MIA. Characterization of the role of this protein in the immune system and intestinal development, as well as in thymic epithelial cells may have important therapeutic implications.

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“…Mouse mutations in the orthologous gene are known and while the mice exhibit some abnormalities in their immune system, they lack a gastrointestinal phenotype. [8][9][10] …”

Section: Introductionmentioning

confidence: 99%

Exome sequencing identifies mutations in the geneTTC7Ain French-Canadian cases with hereditary multiple intestinal atresia

et al. 2013

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BackgroundCongenital multiple intestinal atresia (MIA) is a severe, fatal neonatal disorder, involving the occurrence of obstructions in the small and large intestines ultimately leading to organ failure. Surgical interventions are palliative but do not provide long-term survival. Severe immunodeficiency may be associated with the phenotype. A genetic basis for MIA is likely. We had previously ascertained a cohort of patients of French-Canadian origin, most of whom were deceased as infants or in utero. The goal of the study was to identify the molecular basis for the disease in the patients of this cohort.MethodsWe performed whole exome sequencing on samples from five patients of four families. Validation of mutations and familial segregation was performed using standard Sanger sequencing in these and three additional families with deceased cases. Exon skipping was assessed by reverse transcription-PCR and Sanger sequencing.ResultsFive patients from four different families were each homozygous for a four base intronic deletion in the gene TTC7A, immediately adjacent to a consensus GT splice donor site. The deletion was demonstrated to have deleterious effects on splicing causing the skipping of the attendant upstream coding exon, thereby leading to a predicted severe protein truncation. Parents were heterozygous carriers of the deletion in these families and in two additional families segregating affected cases. In a seventh family, an affected case was compound heterozygous for the same 4bp deletion and a second missense mutation p.L823P, also predicted as pathogenic. No other sequenced genes possessed deleterious variants explanatory for all patients in the cohort. Neither mutation was seen in a large set of control chromosomes.ConclusionsBased on our genetic results, TTC7A is the likely causal gene for MIA.

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A Mutant Mouse with Severe Anemia and Skin Abnormalities Controlled by a New Allele of the Flaky Skin (fsn) Locus

Abstract: Abstract:We found a novel recessive mutation in an inbred strain, INT, that

Cited by 9 publications

References 13 publications

Compound heterozygous mutations in TTC7A cause familial multiple intestinal atresias and severe combined immunodeficiency

Compound heterozygous mutations in TTC7A cause familial multiple intestinal atresias and severe combined immunodeficiency

Whole-exome sequencing identifies tetratricopeptide repeat domain 7A ( TTC7A ) mutations for combined immunodeficiency with intestinal atresias

Exome sequencing identifies mutations in the geneTTC7Ain French-Canadian cases with hereditary multiple intestinal atresia

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