High frequencies of ICF syndrome-like pericentromeric heterochromatin decondensation and breakage in chromosome 1 in a chorionic villus sample.
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Adult↗
Biomedical subjects
C M Tuck-Muller
Publications and source records attributed to C M Tuck-Muller.
The origin of four squirrel monkey cell lines established by karyotype analysis.
The squirrel monkey is a neotropical primate genus which is widely used in biomedical research but includes individual species and subspecies that respond differently to experimental perturbations. GTG-banding patterns of chromosomes 15 and 16, which are distinct among different squirrel monkey species and subspecies, were used to determine the origin of three lung fibroblast cell lines from squirrel monkeys of unknown genetic background (DPSO 114/74, SqMkLu/68, and 7603830) and to confirm the origin of a lymphoblast cell line (GSML) recently established from Guyanese squirrel monkey. DPSO 114/74 cells are from Peruvian squirrel monkey, SqMkLu/68 cells are Bolivian squirrel monkey, and 7603830 cells are from a Peruvian/Bolivian hybrid. Chromosome analysis of GSML cells confirmed that they are from Guyanese squirrel monkey.
Animals↗
DNA hypomethylation and unusual chromosome instability in cell lines from ICF syndrome patients.
The ICF syndrome (immunodeficiency, centromeric region instability, facial anomalies) is a unique DNA methylation deficiency disease diagnosed by an extraordinary collection of chromosomal anomalies specifically in the vicinity of the centromeres of chromosomes 1 and 16 (Chr1 and Chr16) in mitogen-stimulated lymphocytes. These aberrations include decondensation of centromere-adjacent (qh) heterochromatin, multiradial chromosomes with up to 12 arms, and whole-arm deletions. We demonstrate that lymphoblastoid cell lines from two ICF patients exhibit these Chr1 and Chr16 anomalies in 61% of the cells and continuously generate 1qh or 16qh breaks. No other consistent chromosomal abnormality was seen except for various telomeric associations, which had not been previously noted in ICF cells. Surprisingly, multiradials composed of arms of both Chr1 and Chr16 were favored over homologous associations and cells containing multiradials with 3 or >4 arms almost always displayed losses or gains of Chr1 or Chr16 arms from the metaphase. Our results suggest that decondensation of 1qh and 16qh often leads to unresolved Holliday junctions, chromosome breakage, arm missegregation, and the formation of multiradials that may yield more stable chromosomal abnormalities, such as translocations. These cell lines maintained the abnormal hypomethylation in 1qh and 16qh seen in ICF tissues. The ICF-specific hypomethylation occurs in only a small percentage of the genome, e.g., ICF brain DNA had 7% less 5-methylcytosine than normal brain DNA. The ICF lymphoblastoid cell lines, therefore, retain not only the ICF-specific pattern of chromosome rearrangements, but also of targeted DNA hypomethylation. This hypomethylation of heterochromatic DNA sequences is seen in many cancers and may predispose to chromosome rearrangements in cancer as well as in ICF.
5-Methylcytosine↗
Adrenal insufficiency in Smith-Lemli-Opitz syndrome.
We describe three unrelated patients with adrenal insufficiency and RSH or Smith-Lemli-Opitz syndrome (SLOS), a disorder due to deficient synthesis of cholesterol. These patients presented with hyponatremia, hyperkalemia, and decreased aldosterone-to-renin ratio, which is a sensitive measure of the renin-aldosterone axis. All patients had profound serum total cholesterol deficiency (14-31 mg/dl) and marked elevation of 7-dehydrocholesterol (10-45 mg/ dl). Two patients were newborn infants with 46, XY karyotypes and complete failure to masculinize; one of these patients also had cortisol deficiency. Both patients died within 10 days of birth of cardiopulmonary complications while on adrenal replacement therapy. The third patient diagnosed with SLOS at birth presented at age 7months with fever and diarrhea and was noted to have profound hyponatremia. This patient is maintaining normal serum electrolytes on mineralocorticoid replacement. We conclude that adrenal insufficiency may be a previously undetected and treatable manifestation in SLOS. We hypothesize that deficiency of cholesterol, an adrenal hormone precursor, may lead to insufficient synthesis of adrenal steroid hormones.
Adrenal Insufficiency↗
1p microdeletion in sibs with minimal phenotypic manifestations.
We report on two sibs with a paracentric inversion of chromosome 1 [inv(1)(p22.3p34.1)] and a small deletion of the same chromosome (p34.1-->p34.3). They presented with learning disabilities and disturbed conduct but lacked the more severe manifestations usually associated with autosomal chromosome deletion. Born to an alcoholic mother and later placed in foster care because of abuse and neglect, the behavior abnormalities they present are likely to be associated with their traumatic postnatal experience. Microscopic deletions without significant morphological phenotypic expression have been described but are rarely reported. Most reported cases of interstitial deletion of 1p had associated malformations and psychomotor retardation. These sibs may represent the first evidence that deletion of 1p34.1-->1p34.3 may have little impact on the phenotype.
Adolescent↗
Prenatal detection of de novo duplication of the short arm of chromosome 18 confirmed by fluorescence in situ hybridization (FISH).
We present a patient with developmental delay, minor anomalies, and duplication 18p confirmed by fluorescence in situ hybridization with whole chromosome 18 painting probe (Oncor p5218). Our observation confirms the findings of other investigators that duplication 18p is not associated with major malformations.
Chromosomes, Human, Pair 18↗
Hyperlipidemia, insulin-dependent diabetes mellitus, and rapidly progressive diabetic retinopathy and nephropathy in Prader-Willi syndrome with del(15)(q11.2q13).
We report on a white man with Prader-Willi syndrome (PWS) and del(15)(q11.2q13), confirmed by fluorescence in situ hybridization (FISH), who had hyperlipidemia, insulin-dependent diabetes, and the early onset and rapid progression of diabetic retinopathy and nephropathy within 4 years after diagnosis of diabetes. The spectrum of glucose intolerance in patients with PWS is discussed, as well as those references which suggest that the prevalence of hyperlipoproteinemia in this condition may be greater than previously recognized. We suggest the need for clarification of both the prevalence and types of hyperlipoproteinemia, as well as the pathophysiology of glucose intolerance and correlation with molecular cytogenetic findings. We also encourage careful monitoring for diabetic complications to further clarify the prevalence and possible accelerated course of microvascular lesions.
Adult↗
A complex five breakpoint intrachromosomal rearrangement ascertained through two recombinant offspring.
Intrachromosomal rearrangements usually result from three of fewer breaks. We report a complex intrachromosomal rearrangement resulting from five breaks in one chromosome 10 of a phenotypically normal father of two developmentally delayed children. GTG-banding analysis of the father's rearranged chromosome 10 suggested in initial pericentric inversion followed by an insertion from the short arm into the terminal band of the long arm [der(10) (pter-->p13::q21.2-->p12.2::q22.1::-->q26.3::q22.1-->q 21.2::p12.2-->p13::q26.3-->qter)]. To our knowledge, this rearrangement is the most complex ever reported in a single chromosome. Both children inherited a recombinant chromosome 10 with loss of the insertion and the segment distal to it [rec(10)der(pter-->p13: :q21.2-->p12.2::q22.1-->q26.3:)]. Mechanisms for both rearrangements are proposed.
Child↗
Translocation 10;18 in a patient with juvenile neuronal ceroid-lipofuscinosis (Batten disease).
We report the first observation of a chromosome abnormality in a patient with typical juvenile ceroid-lipofuscinosis (NCL), who was found to have an apparently balanced translocation between chromosomes 10 and 18 [t(10;18)(q22.1;q21.1)]. Since juvenile NCL was previously mapped to 16p12, this report raises the possibility of heterogeneity in this form of NCL.
Child↗
Identification of supernumerary ring chromosome 1 mosaicism using fluorescence in situ hybridization.
We report on a 15-year-old black boy with severe mental retardation, multiple congenital anomalies, and a supernumerary ring chromosome mosaicism. Fluorescence in situ hybridization with a chromosome 1 painting probe (pBS1) identified the ring as derived from chromosome 1. The karyotype was 46,XY/47,XY,+r(1)(p13q23). A review showed 8 reports of ring chromosome 1. In 5 cases, the patients had a non-supernumerary ring chromosome 1 resulting in partial monosomies of the short and/or long arm of chromosome 1. In 3 cases, the presence of a supernumerary ring resulted in partial trisomy of different segments of chromosome 1. In one of these cases the supernumerary ring was composed primarily of the centromere and the heterochromatic region of chromosome 1, resulting in normal phenotype. Our patient represents the third report of a supernumerary ring chromosome 1 resulting in abnormal phenotype.
Abnormalities, Multiple↗
De novo dup (5p) in a patient with congenital hypoplasia of the adrenal gland.
We report on a black male child with congenital hypoplasia of the adrenal gland (CHA) with a de novo duplication of 5p [dir dup(5) (p13.3-->p15.1)], confirmed by fluorescence in situ hybridization (FISH). In addition to a characteristic clinical course, the patient has hyperpigmentation (melanoderma) since birth, normal external genitalia, marked elevation of ACTH, and absent response to an IV ACTH challenge. To the best of our knowledge, this is the first case of congenital hypoplasia of the adrenal gland associated with a chromosome abnormality. Reviews of dup (5p) and of our patient suggest that duplication of 5p13.3-pter has only minor phenotypic effect, while duplication of the relatively small critical segment p11-p13.2 apparently causes far more deleterious changes. The concurrence of CHA and dup(5p) in our patient may indicate the possible gene localization of an autosomal form of CHA to either at or near 5p13.3 or 5p15.1.
Adrenal Glands↗
A rapid method for PCR amplification of DNA directly from cells fixed in Carnoy's fixative.
We describe a method for rapid and efficient polymerase chain reaction (PCR) amplification of specific target DNA sequences directly from cells fixed in 3:1 methanol-acetic acid (Carnoy's fixative) for routine cytogenetic analysis. The fixed cells used had been stored at -20 degrees C from a few weeks up to 6 years. Primer sets used correspond to loci on an autosome (retinoblastoma, RB1), as well as the X (Duchenne muscular dystrophy, DMD) and Y (sex-determining region of the Y, SRY) chromosomes. Sizes of amplified products were the expected 400, 251 and 609 bps, respectively. No differences in quality of amplification products were found between PCR templates obtained from fresh tissues or from cells fixed for varying lengths of time in Carnoy's fixative. This technique has the following advantages: (1) it allows retrospective studies of genetic disorders from archived specimens; (2) it requires only a limited number of cells; (3) it is rapid and simple; and (4) it avoids multistep procedures required in extraction of the DNA.
Acetates↗
Isodicentric Y chromosome: cytogenetic, molecular and clinical studies and review of the literature.
Dicentrics are among the most common structural abnormalities of the human Y chromosome. Predicting the phenotypic consequences of different duplications and deletions of dicentric Y chromosomes is usually complicated by varying degrees of mosaicism (45,X cell lines), which may, in some cases, remain undetected. Molecular studies in patients with dicentric Y chromosomes have been few, and only two studies have attempted to determine the presence of SRY (the putative testis-determining factor gene). We report an 18-year-old female with short stature, amenorrhea, hirsutism, hypoplastic labia minora, and clitoromegaly who has a 45,X/46,X,idic(Y)(p11.32)/47,X,idic(Y)(p11.32),idic(Y) (p11.32) karyotype. Southern analysis using Y-specific probes (Y97, 2D6, 1F5, pY3.4) and polymerase chain reaction (PCR) analysis using primers for ZFY and SRY were positive for all loci tested, indicating that almost all of the Y chromosome was present. Our findings and an extensive review of the literature emphasize the importance of molecular analyses of abnormal Y chromosomes before any general conclusions can be reached concerning the relative effects of the Y-chromosome abnormality and mosaicism on sexual differentiation.
Adolescent↗
Lysosomal chitobiase (CTB) and the G-protein gamma 5 subunit (GNG5) genes co-localize to human chromosome 1p22.
Previously isolated human placental cDNA clones represent a fusion of specific RNA sequences encoded by two genes: lysosomal chitobiase (CTB) and G-protein gamma 5 subunit (GNG5, Fisher and Aronson, 1992a, 1992b). Both genes have now been mapped to 1p by PCR analysis of somatic cell hybrids and further refined to 1p22 by fluorescence in situ hybridization (FISH) using a YAC clone that contains both the chitobiase and gamma 5 genes.
Acetylglucosaminidase↗
Confirmation of proximal 1q duplication using fluorescence in situ hybridization.
We report on a boy with excessively wrinkled skin, mild micro/brachycephaly with mild hydrocephalus and slightly small temporal lobes, apparently low-set ears, retro/micrognathia and cleft soft palate (Pierre-Robin anomaly), patent ductus arteriosus and foramen ovale, pulmonary hypoplasia, eventration of the left hemidiaphragm, right cryptorchidism, a sacral dimple, flexion contractures of fingers and knees, and equinovarus deformities of both feet. The infant had a de novo dir dup(1)(pter-->q25::q12-->qter). Partial duplications involving proximal 1q have rarely been reported. Furthermore, this is the first case of proximal duplication of chromosome 1q with unequivocal identification using fluorescence in situ hybridization (FISH) with a chromosome 1 painting probe.
Abnormalities, Multiple↗
SRVX, a sex reversing locus in Xp21.2-->p22.11.
Duplication within Xp21 causes female or intersexual development in human embryos with an XY chromosome complement. We have mapped the responsible gene, SRVX (sex reversal X), in XY-sex-reversed maternal half siblings who had inherited the duplication from their mother. The limited size of the duplication in our cases, relative to its extent in other similar cases, allows assignment of the SRVX locus to Xp21.2-->p22.11. We infer that SRVX is part of a pathway of sex-determining genes that includes SRY and SRA1, the latter recently assigned to chromosome 17q. If mutation of SRA1 or SRVX can reverse the sex of the XY fetus, this would explain why mutation within SRY is found only sporadically in women with XY gonadal dysgenesis.
Adult↗
An HLA-haplotype associated with preeclampsia and intrauterine growth retardation.
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Female↗
Duplication of the short arm of the X chromosome in mother and daughter.
An 11-year-old girl with short stature, mental retardation, and mild dysmorphic features was found to have an inverted duplication of most of the short arm of the X chromosome [dic inv dup(X)(qter-->p22.3::p22.3-->cen:)]. Her mother, who is also short and retarded, carries the same duplication. Fluorescence in situ hybridization with an X chromosome library, and with X centromere-specific alpha satellite and telomere probes, was useful in characterizing the duplication. In most females with structurally abnormal X chromosomes, the abnormal chromosome is inactivated. Although the duplicated X was consistently late replicating in the mother, X chromosome inactivation studies in the proband indicated that in 11% of her lymphocytes the duplicated X was active.
Adult↗