Gene/Protein Disease Symptom Drug Enzyme Compound
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Both sexes of adult mice homozygous for a targeted mutation of the Igf1 gene, encoding insulin-like growth factor 1, are infertile dwarfs (approximately 30% of normal size). The testes are reduced in size less than expected from the degree of dwarfism but sustain spermatogenesis only at 18% of the normal level. The epididymides are overall nearly allometric to the reduced body weight, but the distal regions of the duct, vas deferens, seminal vesicles, and prostate are vestigial. Despite the mutational impact on the epididymis, capacitated sperm are able to fertilize wild type eggs in vitro. It is hypothesized that the infertility of male mutants is caused by failure of androgenization resulting in absence of mating behavior, due to drastically reduced levels of serum testosterone (18% of normal). This hormonal deficiency was correlated with an ultrastructural analysis of mutant Leydig cells revealing a significant developmental delay, while assays in organ culture showed that the basal and LH-stimulated production of testosterone by testicular parenchyma is reduced in comparison with wild type controls. The female mutants fail to ovulate even after administration of gonadotropins, which is apparently the primary cause of their infertility, and possess an infantile uterus that exhibits a dramatic hypoplasia especially in the myometrium. The phenotypic manifestations of the mutation were correlated with the localization of transcripts for insulin-like growth factor I and its cognate receptor in wild type reproductive tissues by in situ hybridization.
Mol Endocrinol 1996 Jul
PMID:Effects of an Igf1 gene null mutation on mouse reproduction. 881 30

Over a nine-year period extending from January 1986 to December 1994, eighteen cases of pernicious anemia occurring in Arabs were diagnosed at King Khalid University Hospital in Riyadh. There were 12 Saudi Arab patients and 6 non-Saudi Arabs. There were 11 males and 7 females. The mean age at presentation was 51 years. The presenting symptoms, laboratory features and the disease pattern were similar to those described in northern European patients in most respects with two possible exceptions. First, the mean age at presentation was lower and second, there was a higher frequency of the antibody to intrinsic factor than previously described in northern Europeans. Both differences have been previously noted in Blacks. Associated autoimmune diseases were identified in two patients, one of whom had diabetes mellitus and vitiligo while the other had a remote history of Graves' disease. One young female patient with primary infertility successfully conceived shortly following the initiation of appropriate cyanocobalamin therapy.
Blood Cells Mol Dis 1996
PMID:Pernicious anemia in Arabs. 893 50

Two nonallelic dwarfing mutations in mice define genes important for pituitary development and function. Mice homozygous for either the Ames (df) or Snell (Pit 1dw) dwarf mutations exhibit severe proportional dwarfism, hypothyroidism, and infertility due to the cytodifferentiation failure of three anterior pituitary cell types: thyrotropes, somatotropes, and lactotropes. Analysis of double heterozygotes and double mutants has provided evidence that the df and dw genes act sequentially in the same genetic pathway. Double heterozygotes had no reduction in growth rate or final adult size. Double homozygotes had essentially the same phenotype as the single mutants and were recovered at the predicted frequency, indicating that there are no previously unrecognized, redundant functions of the two genes. Several lines of evidence demonstrate that df acts earlier in the differentiation pathway than Pit1. The df mutants fail to extinguish expression of the homeobox gene Rpx on embryonic day 13.5 (e13.5), and the size of their nascent pituitary glands is reduced by e14.5. In contrast, Pit1dw mutants down-regulate Rpx appropriately and exhibit normal cell proliferation up to e14.5. The failure to extinguish Rpx and the concomitant hypocellularity of df pituitaries suggest the importance of Rpx repression in lineage-specific cell proliferation before the appearance of lineage-specific markers. Later, Pit-1 and hypothalamic neuropeptides act sequentially to regulate marker gene transcription and cell proliferation. These results establish the time of df action in a cascade of genes that regulate pituitary ontogeny.
Mol Endocrinol 1996 Dec
PMID:The Ames dwarf gene, df, is required early in pituitary ontogeny for the extinction of Rpx transcription and initiation of lineage-specific cell proliferation. 896 Dec 67

Blepharophimosis syndrome (BPES) is an autosomal dominant disorder involving abnormal eyelid development. Cytogenetic and linkage analyses have previously implicated the chromosome 3q23 region in multiple cases of this syndrome. However, in a few cases cytogenetic analyses have implicated other chromosomal regions in this condition. Here we report linkage of BPES in a large Indian pedigree to chromosome 7p13-p21; affected only two-point and multipoint analyses using D7S488, D7S2551 and D7S2562 both showed peak lod scores of 3.61 coincident with D7S2562. Recombinations in affected individuals placed the critical region between D7S488 and D7S629. When both affected and unaffected individuals were considered, a maximum two-point lod score of 3.38 at theta = 0.08 was obtained with D7S2551 while a peak multipoint lod score of 3.64 was obtained between D7S488 and D7S2551. Segregation analysis revealed two unaffected individuals carrying the affected haplotype accounted for the difference in peak, relative to the affected only analysis. The chromosome 7p candidate genes inhibin beta A and epidermal growth factor receptor map outside this region whereas the HOX1 gene cluster may map inside this region. Although BPES is sometimes associated with female infertility due to premature ovarian failure, in the current family affected females were fertile. The current finding together with the previous evidence implicating chromosome 3q2 provides strong evidence that BPES involves locus heterogeneity; this point should be considered when counselling affected families.
Hum Mol Genet 1996 Dec
PMID:Linkage of blepharophimosis syndrome in a large Indian pedigree to chromosome 7p. 896 62

Inherited disorders of the pituitary gonadotropins, LH and FSH, are rare. No mutations of the common alpha-subunit gene have been described. A single case of an FSH beta gene mutation has been reported. This mutation consisted of a two nucleotide deletion that caused a frameshift of codons 61-86 followed by premature termination. A homozygous patient with this mutation presented with primary amenorrhea and infertility. Serum FSH levels were low and LH levels were elevated. A postmenopausal heterozygous relative had subnormal FSH and LH and it was postulated that the mutant FSH beta subunit may have impaired gonadotrope function. Only a single example of an LH beta gene mutation has been described. This case was reported in a male who failed to undergo puberty, had elevated immunoreactive LH, but low bioactive LH and low testosterone. The LH beta gene is a member of the CG beta/LH beta gene cluster that resides on chromosome 19q. No rearrangements or deletions were observed and there was a homozygous substitutions of Gln 54 with Arg. The substituted Gln residue is conserved in each of the glycoprotein hormone beta-subunits. Recombinant mutant LH was expressed in CHO cells and was shown to be immunologically active, but it did not bind to the LH receptor, explaining the absence of bioactivity. This finding suggests that Gln 54 is either a contact site for the receptor or that the mutation alters the conformation of LH to prevent binding to the receptor. The serum LH bio/immuno (B/I) ratio in heterozygotes was 50% of control samples, consistent with normal production and stability of the mutant hormone in vivo. Male heterozygotes exhibited slightly reduced testosterone and only one of four was fertile. Female heterozygotes had regular menses and were fertile. A polymorphic variant of LH has been reported. The variant is prevalent in Finland (24% heterozygotes) and several cases have been reported in Japan. The LH variant consists of two amino acid substitutions (W8R; I15T) that correspond to residues normally found in CG beta. The I15T substitution may introduce a glycosylation site. The variant LH has increased bioactivity, but a reduced serum half-life. It is unclear whether the LH variant is of clinical significance aside from altering immunoactivity in some assays. In addition to gonadotropin mutations, defects in gonadotrope viability (SF-1; DAX-1 mutations) and in GnRH secretion (Kallmann syndrome; SF-1; DAX-1) can also lead to hypogonadotropic hypogonadism (Fig. 1). As noted in other talks, the LH-R and FSH-R are also targets for mutations. Thus, genetic defects have now been identified at each level of the H-P-G axis.
Mol Cell Endocrinol 1996 Dec 20
PMID:Inherited disorders of the gonadotropin hormones. 902 52

The follicle-stimulating hormone (FSH) is essential for normal gametogenesis. In females FSH is required for ovarian development and follicle maturation whereas in males FSH determines Sertoli cell number and quantitatively and qualitatively normal spermatogenesis. FSH action is mediated by a G-protein coupled receptor expressed solely in granulosa and Sertoli cells. The FSH-receptor (FSHR) gene is localized on chromosome 2 p21 and spans a region of 54 kb. It consists of ten exons; exon one to nine encode the large extracellular domain and the transmembrane domain is comprised of exon ten. Mutations in the FSHR gene could severely affect gametogenesis and result in infertility. Therefore screening programs have been initiated, in which patients with disturbed fertility were searched for mutations in the FSHR gene. Several Finnish families were identified displaying an inherited pattern of ovarian dysgenesis, a disease leading to streaky underdeveloped ovaries and primary amenorrhea. By genetic linkage the locus of the genetic defect was confined to chromosome 2 p21. Analysis of the FSHR gene resulted in the identification of a mutation (Ala189Val) homozygous in all affected females. Functional studies revealed that the mutation affects the proper protein folding and thereby inactivates the receptor. In a male patient hypophysectomized because of a pituitary tumor, who despite undetectable serum gonadotropins had normal semen parameters, we hypothesized an activating mutation of the FSHR. Screening of exon ten of the FSHR gene resulted in the identification of a Asp567Gly transition in the third intracytoplasmatic loop. Functional studies resulted in a 1.5-fold increase in basal cAMP production compared to wild type FSHR, indicating that the heterozygous mutation leads to a ligand-independent constitutive activation of the FSHR. This patient provides an exceptional model of nature defining the role of FSH in human spermatogenesis. Mutations of the FSHR might have differential effects in each gender. For example activating mutations have not been described in women, therefore it is not clear whether the constitutive activity of the receptor could disturb normal follicular development resulting in certain infertility.
Mol Cell Endocrinol 1996 Dec 20
PMID:Functional and clinical consequences of mutations in the FSH receptor. 902 56

Mice carrying two t complementary haplotypes (tw5/tw32) are totally sterile. Their spermatozoa have poor motility and fertilize neither zona-intact nor zona-free oocytes, even though they are structurally indistinguishable from control (wild-type) spermatozoa. However, when injected directly into oocytes, these infertile spermatozoa are able to participate in normal development. This suggests that infertility of tw5/tw32 male (spermatozoa) is more likely to be due to poor sperm-oocyte interaction than to genetic incompetence of sperm nuclei.
Mol Reprod Dev 1996 Jun
PMID:Inadequate function of sterile tw5/tw32 spermatozoa overcome by intracytoplasmic sperm injection. 911 21

This paper is a review of the current status of technology for mammalian oocyte growth and development in vitro. It compares and contrasts the characteristics of the various culture systems that have been devised for the culture of either isolated preantral follicles or the oocyte-granulosa cell complexes form preantral follicles. The advantages and disadvantages of these various systems are discussed. Endpoints for the evaluation of oocyte development in vitro, including oocyte maturation and embryogenesis, are described. Considerations for the improvement of the culture systems are also presented. These include discussions of the possible effects of apoptosis and inappropriate differentiation of oocyte-associated granulosa cells on oocyte development. Finally, the potential applications of the technology for oocyte growth and development in vitro are discussed. For example, studies of oocyte development in vitro could help to identify specific molecules produced during oocyte development that are essential for normal early embryogenesis and perhaps recognize defects leading to infertility or abnormalities in embryonic development. Moreover, the culture systems may provide the methods necessary to enlarge the populations of valuable agricultural, pharmaceutical product-producing, and endangered animals, and to rescue the oocytes of women about to undergo clinical procedures that place oocytes at risk.
Mol Reprod Dev 1996 Jun
PMID:Mammalian oocyte growth and development in vitro. 911 26

Spermatogenesis is the process by which immature male germ cells, through a complex series of events involving mitosis, meiosis, and cellular differentiation, eventually become mature spermatozoa capable of fertilizing an ovum. This process involves the developmental progression of male germ cells through a number of spermatogenetic cell types, each of which is characterized by unique features of morphology, cellular associations, and specialized functions. The unique features of each germ cell type are dictated, to a large degree, by the patterns of protein expression characteristic of each cell type. This review will examine two different aspects of the regulated expression of heat shock proteins in spermatogenic cells. First, we will review studies showing that the expression of several different members of both the hsp70 as well as hsp90 families of heat shock proteins is regulated during the differentiation of these cells. Second, we will review studies which have examined the induction of hsp expression in spermatogenic cells following exposure to elevated temperatures. Next, we will review the role of the transcription factors, heat shock factor 1 (HSF1) and HSF2 in the regulation of expression of hsps in the testis. One interesting and unique function of the male reproductive system in many species is the maintenance of the testes at a temperature below that of the other tissues of the animal. The importance of precise thermoregulation of the testis is evidenced by the fact that even slight elevations of scrotal temperature are associated with infertility. The results of recent studies have suggested a potential involvement of the cellular stress response in the mechanism responsible for these inhibitory effects of elevated testis temperature on spermatogenesis. Possible mechanisms are discussed.
Cell Mol Life Sci 1997 Feb
PMID:Regulation of hsp expression during rodent spermatogenesis. 911 7

The present study was conducted to examine the expression of tumor necrosis factor-alpha (TNF-alpha) and its receptors (types I and II, designated TNFR-I and TNFR-II, respectively) in human oocytes and cumulus cells at the mRNA and protein levels. mRNA expression was investigated using a reverse transcriptase-polymerase chain reaction (PCR)/Southern hybridization procedure. DNA-free RNA was isolated from the oocytes/cumulus cells, reverse-transcribed, and PCR-amplified using specific oligonucleotide primers based upon genomic/cDNA sequences. The expected bands of 303 bp and 513 bp were observed in oocytes and cumulus cells using primers based on genomic/cDNA sequences of TNF-alpha and TNFR-II, respectively, that hybridized with specific cDNA probes in Southern blot hybridization procedure. The expected band of 368 bp was not observed in oocytes and cumulus cells using primers based on the TNFR-I cDNA sequence. Similar results were observed for expression at the protein level, as seen by the immunoreactivity of the specific antibodies with the paraformaldehyde-fixed oocytes and cumulus cells in the indirect immunofluorescence technique (IFT). These results indicate that human oocytes and cumulus cells express TNF-alpha and its receptor type II (TNFR-II), and not type I (TNFR-I), both at the mRNA and protein levels. These findings provide further evidence and substantiate the proposed physiologic role of TNF-alpha in ovarian function, and may lead to clinical applications in in vitro fertilization programs and in diagnosis and treatment of infertility in women, especially in cases attributed to ovarian dysfunction.
Mol Reprod Dev 1997 Jun
PMID:Expression of tumor necrosis factor-alpha and its receptors type I and type II in human oocytes. 913 12


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