Species: human
Mutation name: None
type: None
fertility: None
Comment: Jackson et al.(1999) 12 (71%) of the 17 unique APT1 mutations in unrelated ALPS probands occurred in exons 7 to 9, which encode the intracellular portion of FAS. In vitro, activated lymphocytes showed apoptotic defects when exposed to an anti-FAS agonist monoclonal antibody. Similar defects were found in a FAS-negative cell line transfected with cDNAs bearing each of the mutations. In cotransfection experiments, FAS constructs with either intra- or extracellular mutations caused dominant inhibition of apoptosis mediated by wildtype FAS. Among the ALPS-associated FAS mutants, dominant inhibition of apoptosis was much more pronounced in mutants affecting the intracellular, versus extracellular, portion of the FAS receptor. Mutations causing disruption of the intracellular FAS death domain also showed a higher penetrance of ALPS phenotype features in mutation-bearing relatives. Significant ALPS-related morbidity occurred in 44% of relatives with intracellular mutations, versus 0% of relatives with extracellular mutations. Thus, the location of mutations within APT1 strongly influences the development and the severity of ALPS.

Species: human
Mutation name: ALPS
type: naturally occurring
fertility: None
Comment: Fisher et al. (1995) described 5 unrelated children with a rare autoimmune lymphoproliferative syndrome (ALPS) characterized by massive nonmalignant lymphadenopathy, autoimmune phenomena, and expanded populations of TCR-CD3(+)CD4(-)CD8(-) lymphocytes. These findings, suggesting a genetic defect in the ability of T lymphocytes to respond to normal immunoregulatory mechanisms, prompted evaluation of lymphocyte apoptosis. Each child had defective FAS-mediated T lymphocyte apoptosis associated with a unique, deleterious FAS gene mutation. One mutation appeared to cause a simple loss of function; however, 4 others had a dominant-negative phenotype when coexpressed with normal FAS. Patients have one mutated and one normal allele, ruling out a recessive mutation. From 11 families with ALPS, Vaishnaw et al.(1999) studied 8 patients to define mechanisms responsible for defective CD95-mediated apoptosis. Mutations in and around the death domain of CD95 had a dominant-negative effect explained by interference with the recruitment of the signal adaptor protein FADD to the death domain. Intracellular domain (ICD) mutations were associated with a highly penetrant Canale-Smith syndrome phenotype and an autosomal dominant inheritance pattern. In contrast, mutations affecting CD95 extracellular domain (ECD) resulted in failure of extracellular expression of mutant protein or impaired binding to CD95 ligand. These mutations did not have a dominant-negative effect. Martin et al.(1999) showed that local or global alterations in the structure of the cytoplasmic death domain from 9 independent ALPS CD95 death-domain mutations resulted in a failure to bind the FADD/MORT1 signaling protein. Despite heterozygosity for the abnormal allele, lymphocytes from ALPS patients showed markedly decreased FADD association and a loss of caspase recruitment and activation after CD95 crosslinking. These data suggested that intracytoplasmic CD95 mutations in ALPS impair apoptosis chiefly by disrupting death-domain interactions with the signaling protein FADD/MORT1.

Species: human
Mutation name: TEN
type: naturally occurring
fertility: None
Comment: Viard et al. (1998) detected high levels of soluble Fas ligand in sera of patients with toxic epidermal necrolysis (TEN). Keratinocytes of TEN patients produced FasL, which induced keratinic apoptosis. Incubating keratinocytes with intravenous immunoglobulin (IVIG) completely inhibited Fas-mediated keratinocyte apoptosis. A naturally occurring anti-Fas immunoglobulin present in IVIG blocks the Fas receptor and mediates this response.

Species: mouse
Mutation name: gld
type: naturally occurring
fertility: None
Comment: Mutated CD95 and CD95L genes (Sneller et al.,1992)$ A novel lymphoproliferative/autoimmune syndrome resembling murine lpr/gld disease. Sneller MC et al. In mice, the two distinct autosomal recessive genes lpr and gld can induce a syndrome characterized by autoantibody formation and the progressive accumulation of an unusual CD4-CD8- T cell population in peripheral lymphoid tissue. This phenotype does not precisely mirror any human disease. In this report we describe two patients with a progressive lymphoproliferative disorder associated with autoimmunity. The peripheral blood and lymph nodes of these patients contained large numbers of an unusual CD4-CD8- T cell population. These CD4-CD8- T cells express surface markers characteristic of mature peripheral blood T cells (CD3, CD2, CD5), express the alpha/beta form of the T cell receptor, and do not express surface markers characteristic of immature thymocytes (CD1) or NK cells (CD16, CD56). Functionally, these cells exhibited deficient proliferation and lymphokine production upon stimulation with mitogenic antibodies to CD3 or CD2. Both proliferation and lymphokine production could be augmented by co-stimulation with an antibody directed at the CD28 determinant. The clinical and immunological features of this syndrome resemble the lymphoproliferative/autoimmune disease seen in lpr and gld mice.. Oocyte growth and follicular development in KIT-deficient Fas-knockout mice. Moniruzzaman M et al. In mammals, oocyte growth and follicular development are known to be regulated by KIT, a tyrosine kinase receptor. Fas is a member of the death receptor family inducing apoptosis. Here, we investigated germ cell survival, oocyte growth and follicular development in KIT-deficient (W(v)/W(v):Fas(+/+)), Fas-deficient (+/+:Fas(-/-)), and both KIT- and Fas-deficient (W(v)/W(v):Fas(-/-)) mice during fetal and postnatal periods. Further, the ovaries of these mice were transplanted in immunodeficient mice to compare oocyte growth and follicular development under a condition isolated from the extraovarian effects of KIT- and Fas-deficiency. Higher numbers of germ cells were found in the fetal and postnatal ovaries of Fas-deficient mice than in the same-aged wild-type mice. In KIT-deficient mice, ovaries at 13 days postcoitum (dpc) contained 1106+/-72 (n=3) germ cells, but the ovaries contained no oocytes after birth. Twenty-one days after transplantation of the ovaries at 13 dpc, no oocytes/germ cells were found. A higher number of germ cells (3843+/-108; n=3) were observed in the W(v)/W(v):Fas(-/-) genotypes than in W(v)/W(v):Fas(+/+) mice at 13 dpc. Furthermore, W(v)/W(v):Fas(-/-) mice contained 528+/-91 (n=3) oocytes at 2 days, and follicles developed to the antral stage at 14 days of age. After transplantation of fetal and neonatal ovaries from W(v)/W(v):Fas(-/-) mice, increased numbers of growing oocytes and developing follicles were obtained compared with those in 14-day old ovaries in vivo. These results show that oocytes grow and follicles develop without KIT signaling, although KIT might be essential for the survival of germ cells/oocytes in mice.

Species: mouse
Mutation name: lpr
type: naturally occurring
fertility: subfertile
Comment: MRL/MpJ-Fas(lpr) mice show abnormalities in ovarian function and morphology with the progression of autoimmune disease. Otani Y et al. (2015) The immune system is known to affect reproductive function, and maternal-fetal immune tolerance is essential for a successful pregnancy. To investigate the relationship between autoimmune disease and female reproductive function, we performed a comparative analysis of the ovarian phenotypes for C57BL/6 mice, autoimmune disease-prone MRL/MpJ (MRL/+) mice and congenic MRL/MpJ-Fas(lpr) (MRL/lpr) mice harboring a mutation in the Fas gene that speeds disease onset. Both MRL-background strains showed earlier vaginal opening than C57BL/6 mice. The estrous cycle became irregular by 6 and 12 months of age in MRL/lpr mice and mice of the other two strains, respectively. Histological analysis at 3 months revealed that the number of primordial follicles was smaller in MRL-background mice than in C57BL/6 mice after 3 months. In addition, MRL/lpr and MRL/+ mice displayed lower numbers of ovarian follicles and corpora lutea at 3 and 6 months, and 6 and 12 months, respectively, than that in age-matched C57BL/6 mice. MRL/lpr and MRL/+ mice developed ovarian interstitial glands after 3 and 6 months, respectively. In particular, MRL/lpr mice showed numerous infiltrating lymphocytes within the ovarian interstitia, and partially stratified ovarian surface epithelia with more developed microvilli than that observed in C57BL/6 mice at 6 months. No significant differences in serum hormone levels were observed between the strains. In conclusion, MRL/lpr mice display altered ovarian development, morphology and function consistent with the progression of severe autoimmune disease, as these findings are less severe in MRL/+ counterparts.////////////////// Lymphoproliferation (lpr) mutation shows defects in the Fas antigen gene; mice develop lymphadenopathy and suffer from a systemic lupus erythematosus-like autoimmune disease, indicating an important role for Fas antigen in the negative selection of autoreactive T cells in the thymus. The point mutation in the Fas gene in the lpr mouse was a T-to-A transversion causing the substitution of asparagine for isoleucine (Watanabe-Fukunaga et al.,1992). Peripheral activated T cells from lpr/lpr mutant mice that express a reduced number of APO1 receptors have a defect in T-cell receptor (TCR)-induced apoptosis. Recessive mutation (Fisher et al.,1995).