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Biomedical subjects

A R Zinn

Publications and source records attributed to A R Zinn.

At least 19 recordsLinked to original sources
PubMed2002

Most X;autosome translocations associated with premature ovarian failure do not interrupt X-linked genes.

Balanced translocations with breakpoints in a critical region of the X chromosome, Xq13-->q26, are associated with premature ovarian failure (POF). Translocations may cause POF either by affecting expression of specific X-linked genes essential for maintenance of normal ovarian function or by a chromosomal effect such as inhibition of meiotic pairing or altered X inactivation. We previously mapped seven Xq translocation breakpoints associated with POF to approximately 75-kb intervals. One translocation disrupted an aminopeptidase gene, XPNPEP2. We have now refined the map location of the remaining six breakpoints with respect to known genes and transcription units predicted from the draft human genome sequence. Only one of the six breakpoints disrupts a gene, DACH2, the human ortholog of a mouse gene expressed in embryonic nervous tissue, sensory organs, and limbs. DACH2 has no obvious relationship to ovarian function. The other five breakpoints fall in apparently intragenic regions. Our results are most consistent with models for POF associated with X;autosome translocations that involve generalized chromosome effects.

Amino Acid Sequence↗
PubMed2001

A man who inherited his SRY gene and Leri-Weill dyschondrosteosis from his mother and neurofibromatosis type 1 from his father.

We report on a man with neurofibromatosis type 1 (NF1) and Leri-Weill dyschondrosteosis (LWD). His father had NF1. His mother had LWD plus additional findings of Turner syndrome (TS): high arched palate, bicuspid aortic valve, aortic stenosis, and premature ovarian failure. The proband's karyotype was 46,X,dic(X;Y)(p22.3;p11.32). Despite having almost the same genetic constitution as 47,XXY Klinefelter syndrome, he was normally virilized, although slight elevation of serum gonadotropins indicated gonadal dysfunction. His mother's karyotype was mosaic 45,X[17 cells]/46,X,dic(X;Y)(p22.3;p11.32)[3 cells].ish dic(X;Y)(DXZ1 +,DYZ1 + ). The dic(X;Y) chromosome was also positive for Y markers PABY, SRY, and DYZ5, but negative for SHOX. The dic(X;Y) chromosome was also positive for X markers DXZ1 and a sequence < 300 kb from PABX, suggesting that the deletion encompassed only pseudoautosomal sequences. Replication studies indicated that the normal X and the dic(X;Y) were randomly inactivated in the proband's lymphocytes. LWD in the proband and his mother was explained by SHOX haploinsufficiency. The mother's female phenotype was most likely due to 45,X mosaicism. This family segregating Mendelian and chromosomal disorders illustrates extreme sex chromosome variation compatible with normal male and female sexual differentiation. The case also highlights the importance of karyotyping for differentiating LWD and TS, especially in patients with findings such as premature ovarian failure or aortic abnormalities not associated with isolated SHOX haploinsufficiency.

Adult↗
PubMed2001

A fork in the road to fertility.

Haploinsufficiency of FOXL2, a new forkhead transcription factor, causes blepharophimosis/ptosis/epicanthus inversus syndrome (BPES), a rare developmental disorder affecting the eyelid and sometimes the ovary. A new study implicates FOXL2 as the first human gene required for the maintenance of ovarian follicles. The discovery of FOXL2 may provide insight into the causes of idiopathic premature ovarian failure, a disease that burdens many infertile couples.

Blepharophimosis↗
PubMed2001

Molecular analysis of genes on Xp controlling Turner syndrome and premature ovarian failure (POF).

Monosomy X has been known to be the chromosomal basis of Turner syndrome (TS) for more than four decades. A large body of cytogenetic data indicates that most TS features are due to reduced dosage of genes on the short arm of the X chromosome (Xp). Phenotype mapping studies using molecular cytogenetic and genetic techniques are beginning to localize the Xp genes that are important for various TS features, and a comprehensive catalog of candidate genes is becoming available through the Human Genome Project and related research. It is now possible to assess the contributions of individual genes to the TS phenotype by mutational analysis of karyotypically normal persons with specific TS features. This strategy has succeeded in identifying a gene involved in short stature and is being applied to premature ovarian failure and other TS phenotypes.

Body Height↗
PubMed2001

Phenotypes Associated with SHOX Deficiency.

Leri-Weill dyschondrosteosis (LWD) (MIM 127300) is a dominantly inherited skeletal dysplasia characterized phenotypically by Madelung wrist deformity, mesomelia, and short stature. LWD can now be defined genetically by haploinsufficiency of the SHOX (short stature homeobox-containing) gene. We have studied 21 LWD families (43 affected LWD subjects, including 32 females and 11 males, ages 3-56 yr) with confirmed SHOX abnormalities. We investigated the relationship between SHOX mutations, height deficit, and Madelung deformity to determine the contribution of SHOX haploinsufficiency to the LWD and Turner syndrome (TS) phenotypes. Also, we examined the effects of age, gender, and female puberty (estrogen) on the LWD phenotype. SHOX deletions were present in affected individuals from 17 families (81%), and point mutations were detected in 4 families (19%). In the LWD subjects, height deficits ranged from -4.6 to +0.6 SD (mean +/- SD = -2.2 +/- 1.0). There were no statistically significant effects of age, gender, pubertal status, or parental origin of SHOX mutations on height z-score. The height deficit in LWD is approximately two thirds that of TS. Madelung deformity was present in 74% of LWD children and adults and was more frequent and severe in females than males. The prevalence of the Madelung deformity was higher in the LWD vs. a TS population. The prevalence of increased carrying angle, high arched palate, and scoliosis was similar in the two populations. In conclusion, SHOX deletions or mutations accounted for all of our LWD cases. SHOX haploinsufficiency accounts for most, but not all, of the TS height deficit. The LWD phenotype shows some gender- and age-related differences.

Adolescent↗
PubMed2000

The Turner syndrome-associated neurocognitive phenotype maps to distal Xp.

Turner syndrome (TS) is associated with a characteristic neurocognitive profile that includes impaired visuospatial/perceptual abilities. We used a molecular approach to identify a critical region of the X chromosome for neurocognitive aspects of TS. Partial deletions of Xp in 34 females were mapped by FISH or by loss of heterozygosity of polymorphic markers. Discriminant function analysis optimally identified the TS-associated neurocognitive phenotype. Only subjects missing approximately 10 Mb of distal Xp manifested the specified neurocognitive profile. The phenotype was seen with either paternally or maternally inherited deletions and with either complete or incomplete skewing of X inactivation. Fine mapping of informative deletions implicated a critical region of <2 Mb within the pseudoautosomal region (PAR1). We conclude that haploinsufficiency of PAR1 gene(s) is the basis for susceptibility to the TS neurocognitive phenotype.

Adolescent↗
PubMed2000

Profound obesity associated with a balanced translocation that disrupts the SIM1 gene.

Studies of mice and humans have revealed a number of genes that when mutated result in severe obesity. We have studied a unique girl with early-onset obesity and a de novo balanced translocation between chromosomes 1p22.1 and 6q16.2. Her weight gain is most likely due to excessive food intake, since measured energy expenditure was normal. We cloned and sequenced both translocation breakpoints. The translocation does not appear to affect any transcription unit on 1p, but it disrupts the SIM1 gene on 6q. SIM1 encodes a human homolog of Drosophila Sim (Single-minded), a transcription factor involved in midline neurogenesis, and is a prototypical member of the bHLH-PAS (basic helix-loop-helix + period, aryl hydrocarbon receptor, Single-minded) gene family. Our subject's trans- location separates the 5' promoter region and bHLH domain from the 3' PAS and putative transcriptional regulation domains. The transcriptional targets of SIM1 are not known. Mouse Sim1 is expressed in the developing kidney and central nervous system, and is essential for formation of the supraoptic and paraventricular (PVN) nuclei of the hypothalamus. Previous neuroanatomical and pharmacological studies have implicated the PVN in the regulation of body weight: PVN neurons express the melanocortin 4 receptor and appear to be physiological targets of alpha-melanocyte-stimulating hormone, which inhibits food intake. We hypothesize that haploinsufficiency of SIM1, possibly acting upstream or downstream of the melanocortin 4 receptor in the PVN, is responsible for severe obesity in our subject.

Age of Onset↗
PubMed2000

Physical mapping of nine Xq translocation breakpoints and identification of XPNPEP2 as a premature ovarian failure candidate gene.

Women with balanced translocations between the long arm of the X chromosome (Xq) and an autosome frequently suffer premature ovarian failure (POF). Two "critical regions" for POF which extend from Xq13-->q22 and from Xq22-->q26 have been identified using cytogenetics. To gain insight into the mechanism(s) responsible for ovarian failure in women with X;autosome translocations, we have molecularly characterized the translocation breakpoints of nine X chromosomes. We mapped the breakpoints using somatic cell hybrids retaining the derivative autosome and densely spaced markers from the X-chromosome physical map. One of the POF-associated breakpoints in a critical region (Xq25) mapped to a sequenced PAC clone. The translocation disrupts XPNPEP2, which encodes an Xaa-Pro aminopeptidase that hydrolyzes N-terminal Xaa-Pro bonds. XPNPEP2 mRNA was detected in fibroblasts that carry the translocation, suggesting that this gene at least partially escapes X inactivation. Although the physiologic substrates for the enzyme are not known, XPNPEP2 is a candidate gene for POF. Our breakpoint mapping data will help to identify additional candidate POF genes and to delineate the Xq POF critical region(s).

Amino Acid Sequence↗
PubMed1999

New gene family defined by MORC, a nuclear protein required for mouse spermatogenesis.

Mammalian spermatogenesis is a complex developmental process. The analysis of mouse mutations has provided insight into biochemical pathways required for completion of this process. We previously described the autosomal recessive mouse morc TgN(Tyr)1Az(microrchidia) mutation, a serendipitous transgenic insertional mutation which causes arrest of spermatogenesis prior to the pachytene stage of meiosis prophase I. We now report the molecular characterization of the morc locus and positional cloning of a gene disrupted by the morc TgN(Tyr)1Az mutation. This gene, which we term Morc, encodes a 108 kDa protein expressed specifically in male germ cells. The transgene integrated within the first intron of Morc and was accompanied by an intragenic deletion of approximately 13 kb of genomic sequences, removing exons 2-4 and abrogating expression of the wild-type transcript. Analysis of the MORC protein sequence revealed putative nuclear localization signals, two predicted coiled-coil structural motifs and limited homology to GHL (GyraseB, Hsp90, MutL) ATPase. Epitope-tagged MORC protein expressed in COS7 cells localized to the nucleus. We also cloned the human MORC homolog and show that it too is testis-specific, but closely related human genes are transcribed in multiple somatic tissues. Homologous proteins are also present in zebrafish, nematodes, slime mold and plants. Thus, cloning of Morc defines a novel gene family whose members are likely to serve important biological functions in both meiotic and mitotic cells of multicellular organisms.

Amino Acid Sequence↗
PubMed1998

Identification of morc (microrchidia), a mutation that results in arrest of spermatogenesis at an early meiotic stage in the mouse.

The microrchidia, or morc, autosomal recessive mutation results in the arrest of spermatogenesis early in prophase I of meiosis. The morc mutation arose spontaneously during the development of a mouse strain transgenic for a tyrosinase cDNA construct. Morc -/- males are infertile and have grossly reduced testicular mass, whereas -/- females are normal, indicating that the Morc gene acts specifically during male gametogenesis. Immunofluorescence to synaptonemal complex antigens demonstrated that -/- male germ cells enter meiosis but fail to progress beyond zygotene or leptotene stage. An apoptosis assay revealed massive numbers of cells undergoing apoptosis in testes of -/- mice. No other abnormal phenotype was observed in mutant animals, with the exception of eye pigmentation caused by transgene expression in the retina. Spermatogenesis is normal in +/- males, despite significant transgene expression in germ cells. Genomic analysis of -/- animals indicates the presence of a deletion adjacent to the transgene. Identification of the gene inactivated by the transgene insertion may define a novel biochemical pathway involved in mammalian germ cell development and meiosis.

Animals↗
PubMed1998

Turner syndrome and haploinsufficiency.

Turner syndrome was one of the first human genetic disorders ascribed to haploinsufficiency but the identification of specific genes responsible for the phenotype has been problematic. Recent data point to several candidate genes, some new and some old, for specific aspects of the phenotype associated with monosomy X in humans.

Animals↗
PubMed1998

Evidence for a Turner syndrome locus or loci at Xp11.2-p22.1.

Turner syndrome is the complex human phenotype associated with complete or partial monosomy X. Principle features of Turner syndrome include short stature, ovarian failure, and a variety of other anatomic and physiological abnormalities, such as webbed neck, lymphedema, cardiovascular and renal anomalies, hypertension, and autoimmune thyroid disease. We studied 28 apparently nonmosaic subjects with partial deletions of Xp, in order to map loci responsible for various components of the Turner syndrome phenotype. Subjects were carefully evaluated for the presence or absence of Turner syndrome features, and their deletions were mapped by FISH with a panel of Xp markers. Using a statistical method to examine genotype/phenotype correlations, we mapped one or more Turner syndrome traits to a critical region in Xp11.2-p22.1. These traits included short stature, ovarian failure, high-arched palate, and autoimmune thyroid disease. The results are useful for genetic counseling of individuals with partial monosomy X. Study of additional subjects should refine the localization of Turner syndrome loci and provide a rational basis for exploration of candidate genes.

Adolescent↗
PubMed1997

Discriminant analysis of the Ullrich-Turner syndrome neurocognitive profile.

Ullrich-Turner syndrome (UTS), or monosomy X, is a genetic disorder characterized by short stature, gonadal dysgenesis, and a particular neurocognitive profile of normally developed language abilities (particularly verbal IQ) and impaired visual-spatial and/or visual-perceptual abilities. The most frequently described profile in UTS includes difficulty with tasks involving memory and attention, decreased arithmetic skills, and impaired visual spatial processing. We used discriminant function analysis (DFA) to distinguish between the neurocognitive profiles of girls with UTS vs. controls matched for age, height, IQ, and socioeconomic status. DFA is a statistical method for deriving a linear function that optimally weights parameters to permit sensitive and specific differentiation among groups. We developed a modified discriminant function, based on seven cognitive test scores, that successfully discriminated between the UTS and control subjects with a sensitivity of 0.45 and a specificity of 0.97. To validate its performance, we applied the discriminant function to a small group of 45,X UTS subjects (n = 13) and control female subjects (n = 25), ages 7-16 years, who were not part of the previous analyses. The discriminant function (DF) identified 54% of these 13 UTS subjects as having the "UTS neurocognitive profile" and 92% of the 25 control subjects as not having the profile. We also compared the DF scores of UTS girls with various mosaic karyotypes and found that the group with 46,XX mosaicism had significantly higher scores (i.e., closer to normal controls) than the other two mosaic groups (t = 2.86, P < 0.005). The results of this study should be useful for genetic counseling and planning educational programs for girls with UTS.

Adolescent↗
PubMed1997

Prune-belly syndrome and other anomalies in a stillborn fetus with a ring X chromosome lacking XIST.

Ring X chromosomes that lack the X inactivation center and fail to be inactivated have been implicated as a cause of mental retardation and multiple congenital anomalies. We report on a stillborn fetus with karyotype mos45,X/46,X,r(X) and early urethral obstruction or prune-belly sequence, single umbilical artery, limb deficiency, horseshoe kidney, cardiac hypertrophy, persistent left superior vena cava, and axial skeleton abnormalities. Fluorescent in situ hydridization (FISH) studies confirmed that the ring chromosome is X-derived and demonstrated that it lacks the XIST locus. The findings in this fetus are discussed with regard to the spectrum of phenotypes associated with monosomy X and small ring X chromosomes.

Abnormalities, Multiple↗
PubMed1997

Del (X)(p21.2) in a mother and two daughters with variable ovarian function.

We report a family in which a woman with the mosaic karyotype 45,X/46,X,del(X)(p21.2) transmitted the deleted X chromosome to two daughters. The nature of the deletion was confirmed by fluorescent in situ hybridization (FISH). All three family members showed somatic Ullrich-Turner syndrome features, but only one daughter had ovarian failure. These observations have implications for the diagnosis of Ullrich-Turner syndrome and genotype/phenotype correlations of X chromosome deletions.

Abnormalities, Multiple↗
PubMed1994

Structure and function of ribosomal protein S4 genes on the human and mouse sex chromosomes.

The human sex-linked genes RPS4X and RPS4Y encode distinct isoforms of ribosomal protein S4. Insufficient expression of S4 may play a role in the development of Turner syndrome, the complex human phenotype associated with monosomy X. In mice, the S4 protein is encoded by an X-linked gene, Rps4, and is identical to human S4X; there is no mouse Y homolog. We report here the organization of the human RPS4X and RPS4Y and mouse Rps4 genes. Each gene comprises seven exons; the positions of introns are conserved. The 5' flanking sequences of human RPS4X and mouse Rps4 are very similar, while RPS4Y diverges shortly upstream of the transcription start site. In chickens, S4 is encoded by a single gene that is not sex linked. The chicken protein differs from human S4X by four amino acid substitutions, all within a region encoded by a single exon. Three of the four substitutions are also present in human S4Y, suggesting that the chicken S4 gene may have arisen by recombination between S4X- and S4Y-like sequences. Using isoform-specific antisera, we determined that human S4X and S4Y are both present in translationally active ribosomes. S4Y is about 10 to 15% as abundant as S4X in ribosomes from normal male placental tissue and 46,XY cultured cells. In 49,XYYYY cells, S4Y is about half as abundant as S4X. In 49,XXXXY cells, S4Y is barely detectable. These results bear on the hypothesized role of S4 deficiency in Turner syndrome.

Amino Acid Sequence↗