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Biomedical subjects

D H Ledbetter

Publications and source records attributed to D H Ledbetter.

At least 127 records · Page 7Linked to original sources
PubMed1992

X-linked lymphoproliferative disease: prenatal detection of an unaffected histocompatible male.

Chorionic Villous Biopsy (CVS) for diagnosis of XLP was undertaken at 10 weeks gestation in an obligate carrier. The fetus was found to be male by cytogenetic analysis. XLP (Xq25-q26) is closely linked to the RFLP markers DXS10, DXS37 and DXS42, but only DXS10 (distal to XLP) was informative for prenatal diagnosis in this family. RFLP analysis using this marker gave a 7% risk that the fetus was affected, based on the known recombination frequency between DXS10 and XLP. Further investigation was then undertaken to obtain a rapid and more accurate diagnosis using the three highly polymorphic PCR based markers. These were the AC repeat markers DXS424 (XL5A) and DXS425 (XL90A3) and the tetramer repeat marker within HPRT. DX425 is approximately 10 cM proximal to DXS10 and HPRT but is not known with certainty to map proximal or distal to XLP. DXS424 is proximal to DXS10 and HPRT and was inferred to be proximal to XLP on the basis of map distance from HPRT estimated by linkage analysis of data from CEPH pedigrees. This was confirmed by a recombinant in the XLP family between DXS424 and DXS425, placing DXS424 proximal to XLP. Diagnosis by linkage using DXS424 and DXS425, at least one of which is proximal to XLP, and distal markers DXS10 and HPRT, increased the accuracy of diagnosis using flanking marker analysis to greater than 99% that the fetus was unaffected. HLA DR typing of the CVS showed that the fetus was DR identical to a male sibling with XLP. HLA compatibility was confirmed at delivery by full HLA typing and MLC.(ABSTRACT TRUNCATED AT 250 WORDS)

Child, Preschool↗
PubMed1992

An unusual expression of a squamous cell marker, small proline-rich protein gene, in tracheobronchial epithelium: differential regulation and gene mapping.

An unusual expression of a putative squamous cell marker, small proline-rich protein (spr1), in mucociliary epithelial cells of conducting airways was demonstrated in a serum-free culture system. A cDNA clone was isolated from the cDNA library of monkey tracheobronchial epithelial (TBE) cells by differential hybridization. This cDNA clone, MT5, exhibited 98% homology to a DNA sequence obtained from human keratinocytes treated with either UV light or phorbol esters (T. Kartasova et al., 1988, Mol. Cell. Biol. 8:2195-2230). The predicted peptide of MT5 is unusual for its high content of proline (29%), glutamine (18%), and cysteine (9%) and its repeated PKVPEPC units. The level of spr1 mRNA in cultured cells was inhibited more than 90% by vitamin A. In contrast, phorbol 12-myristate 13-acetate (PMA) stimulated the level of spr1 mRNA by 3- to 8-fold. This differential regulation coincided with the effects of these chemicals on the cornification of cultured TBE cells. Using MT5 as a probe, we have localized the tracheal spr1 gene on the human chromosome 1 by a Southern blot analysis using a panel of human-rodent somatic cell hybrid DNAs. The gene was further sublocalized to bands q22-23 by in situ hybridization.

Amino Acid Sequence↗
PubMed1992

Causal heterogeneity in isolated lissencephaly.

We report clinical, cytogenetic, and molecular studies in 65 patients with isolated lissencephaly sequence (ILS). All had type I lissencephaly of varying severity and a grossly normal cerebellum. Some had additional brain abnormalities. Facial appearance was essentially normal. All had severe to profound mental retardation, seizures, hypotonia that evolved into spasticity, and feeding difficulties. Clinical and laboratory studies demonstrated etiologic heterogeneity. Molecular studies detected microdeletions in chromosome band 17p13.3 in six of 44 patients tested, confirming that deletion of all or part of this "critical region" is the cause of ILS in some cases. There were slightly larger deletions in the same region in a majority of patients with Miller-Dieker syndrome. One patient had an apparently balanced, de novo reciprocal translocation with breakpoints at Xq22 and 2p25. Four sibs from two families had a new, autosomal recessive syndrome of ILS with neonatal death. Other causes supported by clinical observations include autosomal recessive inheritance, intrauterine infection, and intrauterine perfusion failure. Those ILS probands in whom no etiology could be established had 41 sibs of whom three were affected, giving an empiric recurrence risk of 7%.

Brain↗
PubMed1992

Microdeletions of chromosome 17p13 as a cause of isolated lissencephaly.

Lissencephaly (agyria-pachygyria) is a brain malformation manifested by a smooth cerebral surface, resulting from arrest of neuronal migration at 10-14 wk gestation. Type I, or classical, lissencephaly can occur either in association with the Miller-Dieker syndrome (MDS) or as an isolated finding, termed "isolated lissencephaly sequence" (ILS). About 90% of MDS patients have visible or submicroscopic deletions of 17p13.3. We therefore investigated the possibility that some ILS patients have smaller deletions in this chromosomal region. Forty-five ILS patients with gyral abnormalities ranging from complete agyria to mixed agyria/pachygyria and complete pachygyria were studied. RFLP analysis with five polymorphic loci in 17p13.3 was performed on all patients and their parents. Somatic cell hybrids were constructed on three patients, to confirm a deletion or to determine the boundaries of a deletion. In-situ hybridization using cosmid probes from within a newly defined lissencephaly critical region was performed on 31 patients as a further method of deletion detection. Six submicroscopic deletions were detected (13.3%). Three of the deletions among 45 ILS patients were detected by RFLP analysis, 4 deletions in 31 patients were detected by in situ hybridization, and one deletion was detected only by somatic cell hybrid studies (in situ hybridization was not performed). Overall, in situ hybridization proved to be the most rapid and sensitive method of deletion detection. The centromeric boundary of these deletions overlapped that of MDS patients, while the telomeric boundary for four ILS deletions was proximal to that of MDS and narrows the critical region for a lissencephaly locus.(ABSTRACT TRUNCATED AT 250 WORDS)

Base Sequence↗
PubMed1992

Maternal uniparental isodisomy of chromosome 14: association with autosomal recessive rod monochromacy.

Rod monochromacy (complete congenital achromatopsia) is inherited as an autosomal recessive trait of unknown genetic location. The disorder is characterized by total absence of color discrimination because retinal cone photoreceptors do not develop; systemic features do not occur. A 20-year-old white female with rod monochromacy presented with short stature (less than 5th percentile), mild developmental delay, premature puberty, small hands and feet (length less than 5th percentile), minimal dysmorphism, and a reproductive history of three consecutive first-trimester miscarriages. Cytogenetic analysis showed 45,XX,rob(14;14) in all 30 cells examined. Southern analysis of DNA from the patient and her phenotypically normal mother and two brothers (her father is deceased) ascertained the parental origin of the 14;14 Robertsonian translocation. Analysis of RFLPs associated with nine VNTR probes and two dinucleotide repeat polymorphisms from chromosome 14 demonstrated that the patient had inherited two copies of a single allele, each of which was maternally derived. A fully informative RFLP analysis of three probes from chromosome 14 enabled reconstruction of the paternal haplotype and showed the lack of any paternal contribution to the subject. These data are consistent with maternal isodisomy for all portions of chromosome 14 tested by these markers. This finding suggests that rod monochromacy maps to chromosome 14, and it emphasizes the importance of uniparental isodisomy to provide a putative chromosomal assignment of a gene for a rare autosomal recessive disorder.

Chromosome Mapping↗
PubMed1992

Localization of the photoreceptor gene ROM1 to human chromosome 11 and mouse chromosome 19: sublocalization to human 11q13 between PGA and PYGM.

Rom-1 is a retinal integral membrane protein that, together with the product of the human retinal degeneration slow gene (RDS), defines a photoreceptor-specific protein family. The gene for rom-1 (HGM symbol: ROM1) has been assigned to human chromosome 11 and mouse chromosome 19 by Southern blot analysis of somatic cell hybrid DNAs. ROM1 was regionally sublocalized to human 11p13-11q13 by using three mouse-human somatic cell hybrids; in situ hybridization refined the sublocalization to human 11q13. Analysis of somatic cell hybrids suggested that the most likely localization of ROM1 is in the approximately 2-cM interval between human PGA (human pepsinogen A) and PYGM (muscle glycogen phosphorylase). ROM1 appears to be a new member of a conserved syntenic group whose members include such genes as CD5, CD20, and OSBP (oxysterol-binding protein), on human chromosome 11 and mouse chromosome 19. Localization of the ROM1 gene will permit the examination of its linkage to hereditary retinopathies in man and mouse.

Animals↗
PubMed1991

Interstitial deletion of chromosome 18[del(18)(q11.2q12.2 or q12.2q21.1].

A 27-month old boy with mild developmental delay, growth delay, strabismus, midface hypoplasia, relative telecanthus, downslanting palpebral fissures, epicanthal folds, dental hypoplasia, and cardiac defects was found to have an interstitial deletion of chromosome 18 involving band q12.1 or q12.3

Abnormalities, Multiple↗
PubMed1991

Di George anomaly associated with a de novo Y;22 translocation resulting in monosomy del(22)(q11.2).

We report on an infant, born to a diabetic mother, who presented with hypocalcemia and congenital heart disease, presurgically diagnosed by echocardiography as truncus arteriosus type I. Cytogenetic analysis showed a 45,X,-Y,-22,+der-(Y)t(Y;22) (p11.3q11.2) chromosome abnormality with del(22)(q11.2). Parental chromosomes were normal. Autopsy showed persistent truncus arteriosus type II and thymic aplasia consistent with DiGeorge anomaly. This report adds to the existing literature demonstrating an association between DiGeorge anomaly and monosomy 22q11.

Chromosome Aberrations↗
PubMed1991

Genetic analysis of indefinite division in human cells: evidence for a cell senescence-related gene(s) on human chromosome 4.

Earlier studies had demonstrated that fusion of normal with immortal human cells yielded hybrids having limited division potential. This indicated that the phenotype of limited proliferation (cellular senescence) is dominant and that immortal cells result from recessive changes in normal growth-regulatory genes. In additional studies, we exploited the fact that the immortal phenotype is recessive and, by fusing various immortal human cell lines with each other, identified four complementation groups for indefinite division. Assignment of cell lines to specific groups allowed us to take a focused approach to identify the chromosomes and genes involved in growth regulation that have been modified in immortal cells. We report here that introduction of a normal human chromosome 4 into three immortal cell lines (HeLa, J82, T98G) assigned to complementation group B resulted in loss of proliferation and reversal of the immortal phenotype. No effect on the proliferation potential of cell lines representative of the other complementation groups was observed. This result suggests that a gene(s) involved in cellular senescence and normal growth regulation resides on chromosome 4.

Base Sequence↗
PubMed1991

Localization of the X inactivation centre on the human X chromosome in Xq13.

X-chromosome inactivation results in the strictly cis-limited inactivation of many but not all genes on one of the two X chromosomes during early development in somatic cells of mammalian females. One feature of virtually all models of X inactivation is the existence of an X-inactivation centre (XIC) required in cis for inactivation to occur. This concept predicts that all structurally abnormal X chromosomes capable of being inactivated have in common a defineable region of the X chromosome. Here we report an analysis of several such rearranged human X chromosomes and define a minimal region of overlap. The results are consistent with models invoking a single XIC and provide a molecular foothold for cloning and analysing the XIC region. One of the markers that defines this region is the XIST gene, which is expressed specifically from inactive, but not active, X chromosomes. The localization of the XIST gene to the XIC region on the human X chromosome implicates XIST in some aspect of X inactivation.

Chromosome Mapping↗
PubMed1991

Greig syndrome associated with an interstitial deletion of 7p: confirmation of the localization of Greig syndrome to 7p13.

An 11-month-old infant with Greig cephalopolysyndactyly syndrome and mild developmental delay is described. High-resolution chromosomal analysis showed a de novo interstitial deletion of chromosome 7p with breakpoints located at p13 and p14. Cytogenetic analysis of polymorphisms of the heterochromatin in the pericentromeric region suggested the deleted chromosome was of paternal origin. This case confirms the localization of Greig syndrome to 7p13 and emphasizes the importance of performing cytogenetic studies on patients with Mendelian disorders who have unusual findings or cognitive abnormalities in a disorder usually associated with normal intellect. Review of clinical features in published reports of patients with a deletion involving 7p13 showed a number to have features overlapping with Greig syndrome. Because of this, we suggest that cytogenetic aberrations, particularly chromosomal microdeletions, may represent a significant etiology for Greig syndrome.

Abnormalities, Multiple↗
PubMed1991

Isodicentric X chromosome in a patient with Turner syndrome--implications for localization of the X-inactivation center.

Cytogenetic analyses have previously shown that the region Xq11.2-q21 is retained in all structurally abnormal X chromosomes. From these observations the conclusion has been drawn that this "critical region" on the proximal long arm of the X chromosome contains the locus controlling X-inactivation. Structurally abnormal X chromosomes without the X-inactivation center would allow nullisomy, disomy, or trisomy for genes on the X chromosome, and this condition is presumed nonviable. We studied a 28-year-old woman with primary amenorrhea and features of Turner syndrome who had an unusual isodicentric chromosome of the short arm of X. This patient provided us with the opportunity to more closely define the location of the X-inactivation center. High resolution chromosome analysis showed a 46,X,idic(X)(pter----q13.2::q13.2----pter) chromosome pattern in 94% of her cells and a 45,X complement in 6%. Replication studies showed this derivative X chromosome to be late-replicating (inactive) in all cells analyzed. DNA analysis confirmed the breakpoint of the isodicentric chromosome to be proximal to PGK1. Based on these results, the locus for the X-inactivation center can be refined to be within Xq11.2-q13.2.

Adult↗
PubMed1991

Molecular characterization of a patient with del(1)(q23-q25).

We report a patient (S.T.) with multiple congenital anomalies and developmental delay associated with an interstitial deletion of 1q23-1q25. Molecular analysis of the deletion was performed using DNA markers that map to 1q. Five DNA markers, MLAJ-1 (D1S61), CRI-L1054 (D1S42), HBI40 (D1S66), OS-6 (D1S75), and BH516 (D1S110), were demonstrated to be deleted. Informative polymorphisms demonstrated this to be a de novo deletion of the maternally derived chromosome. Deletion status was determined using restriction fragment length polymorphism (RFLP) analysis supplemented with densitometry in the experiments where RFLP analysis was not fully informative. Deletions were confirmed by Southern analysis using genomic DNA from a somatic cell hybrid retaining the del(1)(q23-q25) chromosome that was constructed from patient S.T. Flow karyotyping confirmed the deletion and estimated that the deletion encompassed 11,000-16,000 kb. The clinical and cytogenetic characteristics of S.T. are compared with those of ten previously described patients with monosomy 1q21-1q25.

Abnormalities, Multiple↗
PubMed1991

Determination of the origin of nondisjunction in a 49,XXXXY male using hypervariable dinucleotide repeat sequences.

We present a patient with a 49,XXXXY chromosome constitution in whom the origin of the extra X chromosomes was determined by analysis of five polymorphic CA (or GT) dinucleotide repeat sequences. This class of DNA marker has recently been demonstrated to be hypervariable with heterozygosity values up to 80%. By polymerase chain reaction (PCR) analysis of the dinucleotide repeat length polymorphisms, we have shown that all four X chromosomes were of maternal origin.

Abnormalities, Multiple↗
PubMed1991

Chromosomal assignment of a large tRNA gene cluster (tRNA(Leu), tRNA(Gln), tRNA(Lys), tRNA(Arg), tRNA(Gly)) to 17p13.1.

A cluster of tRNA genes (tRNA(UAGLeu), tRNA(CUGGln), tRNA(UUULys), tRNA(UCUArg)) and an adjacent tRNA(GCCGly) have been assigned to human chromosome 17p12-p13.1 by in situ hybridization using a 4.2 kb human DNA fragment for tRNA(Leu), tRNA(Gln), tRNA(Lys), tRNA(Arg), and, for tRNA(Gly), 1.3 kb and 0.58 kb human DNA fragments containing these genes as probes. This localization was confirmed and refined to 17p13.100-p13.105 using a somatic cell hybrid mapping panel. Preliminary experiments with the biotinylated tRNA Leu, Gln, Lys, Arg probe and metaphase spreads from other great apes suggest the presence of a hybridization site on the long arm of gorilla (Gorilla gorilla) chromosome 19 and the short arm of orangutan (Pongo pygmaeus) chromosome 19 providing further support for homology between HSA17, GGO19 and PPY19.

Animals↗
PubMed1991

Tumor suppression by chromosome 11 is not due to cellular senescence.

Previous hybrid studies involving fusion of normal with immortal human cells indicated that the phenotype of cellular senescence is dominant and that immortality results from recessive changes in normal growth regulatory genes. We have further assigned 28 different immortal human cell lines to at least four complementation groups for indefinite division. In order to identify the chromosomes involved in regulating cell proliferation, we have introduced single human chromosomes by microcell fusion into immortal human cells representative of the different complementation groups. Our results demonstrate that the introduction of chromosome 11, implicated in tumor suppression, does not cause cellular senescence in three different immortal human cell lines tested.

Animals↗