FEM1A and FEM1B: novel candidate genes for polycystic ovary syndrome.

BACKGROUND: Human homologs (FEM1A, FEM1B, FEM1C) of nematode sex determination genes are candidate genes for polycystic ovary syndrome (PCOS). We previously identified a FEM1A mutation (H500Y) in a woman with PCOS; FEM1B has been implicated in insulin secretion. METHODS: Women with and without PCOS (287 cases, 187 controls) were genotyped for H500Y and six FEM1A single nucleotide polymorphisms (SNPs), five FEM1B SNPs and five FEM1C SNPs. SNPs and haplotypes were determined and tested for association with PCOS and component phenotypes. RESULTS: No subject carried the FEM1A H500Y mutation. FEM1A SNPs rs8111933 (P = 0.001) and rs12460989 (P = 0.046) were associated with an increased likelihood of PCOS whereas FEM1A SNP rs1044386 was associated with a reduced probability of PCOS (P = 0.013). FEM1B SNP rs10152450 and a linked SNP were associated with a reduced likelihood of PCOS (P = 0.005), and lower homeostasis model assessment (HOMA) for beta-cell function (HOMA-%B, P = 0.011) and lower HOMA for insulin resistance (HOMA-IR, P = 0.018). FEM1B SNP rs12909277 was associated with lower HOMA-%B (P = 0.008) and lower HOMA-IR (P = 0.037). Haplotype associations were consistent with SNP results, and also revealed association of FEM1B haplotype TGAGG with increased HOMA-%B (P = 0.007) and HOMA-IR (P = 0.024). FEM1C variants were not associated with PCOS. CONCLUSIONS: This study presents evidence suggesting a role for FEM1A and FEM1B in the pathogenesis of PCOS. Only FEM1B variants were associated with insulin-related traits in PCOS women, consistent with prior evidence linking this gene to insulin secretion. Replication of these associations and mechanistic studies will be necessary to establish the role of these genes in PCOS.

Colorectal cancer in Russian-speaking Jewish emigrés: community-based screening.

OBJECTIVES: Colorectal cancer (CRC) screening by fecal occult blood testing and flexible sigmoidoscopy is recommended by many authorities for those older than age 50. Ashkenazi Jews have been shown to have a higher level of CRC and polyps than the general population. A subset of Ashkenazi Jews, Russian-speaking Jewish immigrants to the United States (RJIs), have not been studied extensively for CRC and may have additional risk factors not found in other Ashkenazi populations. METHODS: A retrospective chart review was undertaken of fecal occult blood tests, endoscopy reports, and pathology reports of 132 RJIs and 124 non-RJI controls over age 50 between 1987 and 1999 at the Jewish Hospital of Cincinnati Medical Outpatient Clinic. RESULTS: Mean ages at the time of diagnosis or flexible sigmoidoscopy were 68 yr for RJIs and 66 yr for the non-RJI patients. Of the RJI patients, 38.7% had positive findings: 37 (28.0%) with lesions < 2 cm, five (3.8%) with lesions > 2 cm, and nine (6.8%) with CRC. Of the non-RJI control group patients, 16.9% had positive findings: 16 (12.9%) with lesions < 2 cm, three (2.4%) with lesions > 2 cm, and two (1.6%) with CRC. Age- and sex-matched statistical analysis revealed significantly greater CRC and significantly more polyps > 2 cm for the RJI patients (p < 0.003). This is higher than in other studies of Ashkenazis, which show a 2.3% incidence, and in statistics from the National Cancer Institute, which reveal a national CRC incidence rate for those over age 65 to be 0.30%. CONCLUSIONS: RJIs in our study have polyps > 2 cm and CRC at a rate of 10.6%, as compared with 4.0% for in-clinic controls and a national average of 0.30% for patients over age 65. This suggests a need for more aggressive screening of this patient population for CRC.

The oncogenic properties of the HMG-I gene family.

The HMG-I gene family encodes high mobility group proteins originally identified as nonhistone chromosomal binding proteins. HMG-I and -Y proteins are alternatively spliced products of the same mRNA; HMG-C is encoded by a separate gene. The HMG-I proteins function as architectural chromatin-binding proteins that bind to the narrow groove of AT-rich regions in double-stranded DNA. Recent studies indicate an important role for HMG-I proteins in regulating gene expression. Moreover, increased expression of the HMG-I, -Y, and -C proteins correlates with cellular proliferation and neoplastic transformation in several cell types and human cancers. Previous work from our laboratory has shown that HMG-I is a direct c-Myc target gene that is involved in Myc-mediated neoplastic transformation. In this report, we show that increased expression of HMG-Y or -C leads to transformation with anchorage-independent cell growth in two experimental cell lines in a manner similar to that of HMG-I or c-Myc. Moreover, Rat la cells overexpressing HMG-Y or -C form tumors in nude mice analogous to Rat 1a cells overexpressing HMG-I or c-Myc. Distant metastases developed in animals injected with cells overexpressing HMG-I or -C. Our findings suggest that the HMG-I gene family is involved in neoplastic transformation and may represent a new family of oncogenes important in the pathogenesis of several human cancers.

HMG-I/Y, a new c-Myc target gene and potential oncogene.

The HMG-I/Y gene encodes the HMG-I and HMG-Y proteins, which function as architectural chromatin binding proteins important in the transcriptional regulation of several genes. Although increased expression of the HMG-I/Y proteins is associated with cellular proliferation, neoplastic transformation, and several human cancers, the role of these proteins in the pathogenesis of malignancy remains unclear. To better understand the role of these proteins in cell growth and transformation, we have been studying the regulation and function of HMG-I/Y. The HMG-I/Y promoter was cloned, sequenced, and subjected to mutagenesis analysis. A c-Myc-Max consensus DNA binding site was identified as an element important in the serum stimulation of HMG-I/Y. The oncoprotein c-Myc and its protein partner Max bind to this site in vitro and activate transcription in transfection experiments. HMG-I/Y expression is stimulated by c-Myc in a Myc-estradiol receptor cell line in the presence of the protein synthesis inhibitor cycloheximide, indicating that HMG-I/Y is a direct c-Myc target gene. HMG-I/Y induction is decreased in Myc-deficient fibroblasts. HMG-I/Y protein expression is also increased in Burkitt's lymphoma cell lines, which are known to have increased c-Myc protein. Like Myc, increased expression of HMG-I protein leads to the neoplastic transformation of both Rat 1a fibroblasts and CB33 cells. In addition, Rat 1a cells overexpressing HMG-I protein form tumors in nude mice. Decreasing HMG-I/Y proteins using an antisense construct abrogates transformation in Burkitt's lymphoma cells. These findings indicate that HMG-I/Y is a c-Myc target gene involved in neoplastic transformation and a member of a new class of potential oncogenes.

Rapid communication: the human FEM1B gene maps to chromosome 15q22 and is excluded as the gene for Bardet-Biedl syndrome, type 4.

We have identified a novel human gene, FEM1B, that encodes a protein virtually identical to that encoded by the mouse gene Fem1b. These mammalian proteins are homologs of the FEM-1 protein of Caenorhabditis elegans, which acts as a signal-transduction component within the nematode sex-determination pathway. We report here the mapping of FEM1B to chromosome 15q22, a region that is homologous to the region of mouse chromosome 9, where Fem1b resides. The BBS4 locus, one of the loci causing the autosomal recessive Bardet-Biedl syndrome, maps to this region of chromosome 15. Therefore, we sought to determine whether the FEM1B gene might be involved in this disorder. Radiation hybrid mapping demonstrates that FEM1B does not reside within the interval of chromosome 15 containing the BBS4 locus.

Sequence, organization, and expression of the human FEM1B gene.

The FEM-1 protein of Caenorhabditis elegans functions within the nematode sex-determination pathway. Two mouse homologs, encoded by the Fem1a and Fem1b genes, have been reported. We report here the characterization of a novel human gene, designated FEM1B, that is highly homologous to the mouse Fem1b gene. FEM1B encodes a protein, designated FEM1beta, that shows >99% amino acid identity to the corresponding mouse Fem1b protein, including 100% amino acid identity in the N-terminal ANK repeat domain. FEM1beta represents the first characterized human member of the FEM-1 protein family. The human and mouse genes show conservation of coding sequence and its intron/exon organization, flanking untranslated and genomic sequences, and expression pattern in adult tissues. These findings suggest that there may be evolutionary conservation of regulation and function between the mouse and human FEM1B genes.

Thermal cautery after chalazion surgery and its effect on recurrence rates.

BACKGROUND: Chalazion surgery is a common minor surgical procedure used to treat internal chalazia after conservative measures have failed. Complications are infrequent and generally easily managed with minimal problems. In this clinical research study, 100 internal chalazia surgical candidates were randomly divided into two treatment groups. Our initial goal was to ascertain whether cautery impacted the recurrence rates on chalazia in these patients. One group received thermal cautery after surgical incision and drainage. The second group did not receive cautery after incision and drainage. Lack of cautery caused no problems with hemostasis because bleeding resolved without incident after several additional minutes. METHODS: The study was conducted on 100 patients who received 4 weeks of conservative treatment consisting of alternating warm and cold compresses and topical prednisolone acetate/sulfa medication (e.g., blephamide) administered 4 times a day. A transconjunctival incision and drainage was performed, followed by thermal cautery in one-half (N = 50) of the randomized patients. RESULTS: The cauterized group had a 78% no recurrence rate after 6 months and good surgical outcomes. The remaining 22% had a recurrence of chalazia, but with good initial surgical outcome. The noncauterized group (N = 50) showed a 74% no recurrence rate after 6 months and good surgical outcome. The remaining 26% had recurrences with good initial surgical outcomes. A chi-square test indicated that there was no significant statistical difference between the groups (chi2 = 0.219, dF = 1.0, p = 0.640). CONCLUSION: The results of this clinical study suggest that the use of thermal cautery with surgery has no impact on the recurrence rate of internal chalazia. Thus, the use of thermal cautery should be left to the discretion of the eye care practitioner.

The murine fem1 gene family: homologs of the Caenorhabditis elegans sex-determination protein FEM-1.

The pathway controlling sex determination in the nematode Caenorhabditis elegans is a model for the genetic control of cell-fate determination. We report here the cloning and characterization of a new mouse gene family with homology to FEM-1, a signal-transducing regulator in the C. elegans sex-determination pathway. This gene family consists of two known members, designated Fem1a and Fem1b. The highest degree of homology between the two mouse proteins and the nematode protein is in a domain that encodes seven sequential ANK repeats. The Fem1a gene localizes to chromosome 17 and is highly expressed in adult heart and skeletal muscle. The Fem1b gene localizes to chromosome 9 and is highly expressed in adult testis. Both genes are expressed during embryogenesis. The existence of FEM-1 homologs in the mouse raises the possibility that evolutionary conservation of ancient FEM-1 signaling interactions may play a role in vertebrate cell-fate determination.

Long-term use of high-dose benzoate and dextromethorphan for the treatment of nonketotic hyperglycinemia.

OBJECTIVE: The objective of this study was to test the hypotheses that reduction of glycine and blocking of the N-methyl-D-aspartate receptor channel complex would be beneficial for both seizure reduction and developmental progress in patients with nonketotic hyperglycinemia. METHODS: We administered benzoate (at doses of 500 to 750 mg/kg/day) and dextromethorphan (at doses of 3.5 to 22.5 mg/kg/day) to four infants with nonketotic hyperglycinemia with follow-up of 3 months to 6 years. RESULTS: Benzoate reduced to normal the glycine concentration in plasma and substantially reduced but did not normalize the glycine concentration in cerebrospinal fluid. Dextromethorphan was a potent anticonvulsant in some but not all patients. There was remarkable interpatient variability in dextromethorphan metabolism. Three patients are living (ages ranging from 4 to 6 years) and are moderately to severely developmentally delayed; two are free of seizures. The third patient, with the slowest development, had intractable seizures for nearly a month before diagnosis, and although seizure-free for 30 months, now has grand-mal seizures. One patient died of intractable seizures at 3 months. CONCLUSIONS: These outcomes suggest that benzoate and dextromethorphan are not uniformly effective in nonketotic hyperglycinemia, but for some patients they improve arousal, decrease or eliminate seizures, and allow for some developmental progress. Trials with additional patients and other receptor channel blockers are warranted.

Multivalent DNA-binding properties of the HMG-1 proteins.

HMG-I proteins are DNA-binding proteins thought to affect the formation and function of transcription complexes. Each protein contains three DNA-binding motifs, known as AT-hooks, that bind in the minor groove of AT tracts in DNA. Multiple AT-hooks within a polypeptide chain should contact multiple AT tracts, but the rules governing these interactions have not been defined. In this study, we demonstrate that high-affinity binding uses two or three appropriately spaced AT tracts as a single multivalent binding site. These principles have implications for binding to regulatory elements such as the interferon beta enhancer, TATA boxes, and serum response elements.

High-resolution genetic mapping of the cartilage-hair hypoplasia (CHH) gene in Amish and Finnish families.

We recently assigned the gene for cartilage-hair hypoplasia (CHH) to chromosome 9 in Finnish families. Here we have extended and refined our previous linkage analyses by studying 22 Amish and 15 Finnish CHH families and by testing additional markers. The CHH gene maps to 9p in both series and shows no evidence of heterogeneity either within or between the populations. CHH is very closely linked to marker locus D9S163, with no recombinations observed and a combined maximum multipoint lod score of 26.30 for a location at D9S163. Although the odds against a location of the CHH gene between two more distal marker loci, D9S52 and D9S165, are only 48:1, the evidence provided by an observed recombination between the CHH locus and D9S165 and haplotype data at D9S165 and D9S163 in the Amish families allow this interval to be excluded as the location of CHH. We observed strong allelic association between CHH and D9S163 in both Amish and Finnish families, confirming the likely location of the CHH gene very close to this marker. Haplotype analysis of D9S163 and D9S165 in the Amish families suggests that only one mutation accounts for most CHH cases among them, as was expected and as is the case in Finland. Our data do not support the previously suggested hypothesis of a reduced penetrance as an explanation for the deficiency of affected children in the Amish families. We conclude that CHH is a single disease entity in the Amish and Finnish families and that the CHH gene is very close to D9S163 in 9p21-p13.

Diabetic nephropathy: early detection, prevention and management.

Diabetic nephropathy typically presents more than a decade after diagnosis of diabetes and correlates with the duration of poorly controlled disease. Diabetic nephropathy begins as glomerular hypertension and hyperfiltration, followed by microalbuminuria and the development of hypertension, overt proteinuria, nephrotic syndrome, and a progressive decline in the glomerular filtration rate. Increasing expansion of the glomerular mesangium correlates with loss of function, resulting in uremia. This process eventually leads to the need for dialysis or renal transplantation in 30 percent of patients with insulin-dependent diabetes. By lowering intraglomerular pressure through enhanced glycemic control, inhibition of angiotensin and limitation of protein intake, severe nephropathy may be prevented, delayed or even partially reversed. Treatment must stress control of hypertension.

The comprehension of nephrology in America a century ago.

In America 100 years ago, the leading clinician pathologists had an understanding of nephrology comparable to that in Europe. Emphasis was on clinical observations devoid of modern clinical laboratory assistance, but verified or disproved at autopsy. The clinician often functioned as the pathologist for his own patients, and although microscopy had been introduced a few decades earlier and many had the benefit of some training in Germany or elsewhere in Europe, diagnostic capabilities remained limited. Renal physiology and pathophysiology were at best embryonic in the United States and elsewhere. The frequency and severity of medical renal diseases maintained the interest of some of the most astute physicians of the late 19th century; however, they had to remain frustrated by their inadequate diagnostic and, especially, therapeutic ability.

The origins of American nephrology (1800-1850).

Within a few years of its occurrence, American clinicians became aware of the discovery by Bright in 1827 that albuminuria in edematous patients was associated with granular degeneration of the kidney. Yet, there was a paucity of important original observations in nephrology from American in the first half of the 19th century. By the mid-19th century, however, the primitive concepts of clinical nephrology, renal physiology, and renal pathology were becoming established in the United States, after enlightenment from Europe. Because of the dreadful course of anasarca and uremia and stimulated by the advantages of innovations in microscopy, renal disease began at that time to attract the attention of eminent American clinician-pathologists. Their early observations would add to the knowledge base on which later developments such as bacteriology, radiology, clinical chemistry, and other scientific advances would build.