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Biomedical subjects

I Hansmann

Publications and source records attributed to I Hansmann.

At least 19 recordsLinked to original sources
PubMed2002

Paternal isodisomy 7q secondary to monosomy 7 at recurrence in a Down syndrome child with acute myelogenous leukemia.

We report a boy with Down syndrome and leukemia who acquired uniparental isodisomy of chromosome 7q as a secondary chromosomal change during recurrence of the disease. His karyotype before therapy was 46,XY,der(1)t(1;1)(p36;q32),-7,+21c/46,idem,del(9)(p22), whereas at recurrence it was 46,XY,der(1)t(1;1)(p36;q32,-7,der(7)(qter-->p22 through pter::q10-->qter),del(9)(p22),+21c/47,XY,+21c. By using polymerase chain reaction amplification of D7S493 and D7S527 markers, we identified the loss of the maternal chromosome 7 with a consequent paternal isodisomy in the clone with dup7q. This rearrangement could be implicated in the progression of the disease by causing (1) nullisomy for a gene or genes located on 7p22-->pter, (2) functional double doses of exclusively paternal expressed genes, and (3) restoration of the effects produced by haploinsufficiency of biparental expressed genes.

Child, Preschool↗
PubMed2001

Alagille syndrome associated with a paracentric inversion 20p12.2p13 disrupting the JAG1 gene.

Mutations in the human gene Jagged1 (JAG1) localized in 20p12 have been recently identified as causal for the anomalies found in patients with Alagille syndrome (AGS). This gene encodes a ligand for the Notch1 transmembrane receptor, which plays a key role in cell-to-cell signaling during differentiation and is conserved from C. elegans to human. We report a paracentric inversion (PAI) of chromosome 20p12.2p13 in an individual with AGS who also had alpha-1-antitrypsin deficiency. To our knowledge, this is the first published case of PAI involving the short arm of chromosome 20. Using FISH, fiberFISH, and molecular studies with a approximately 40 kb cosmid clone encompassing the entire 36 kb JAG1 gene, we demonstrate that the gene was disrupted by the inversion breakpoint between exons 5 and 6. An unusual association between two most common causes of chronic liver disease in childhood, AGS and alpha-1-antitrypsin deficiency, as well as their influence on the proband's abnormal phenotype are discussed.

Alagille Syndrome↗
PubMed2001

Phenotypic findings due to trisomy 7p15.3-pter including the TWIST locus.

We report on a three-month-old boy with a 46,XY,der(Y)t(Y;7)(p11.32;p15.3) karyotype and growth deficiency, postnatal microcephaly with large fontanels, wide sagittal and metopic sutures, hypertelorism, choanal stenosis, micrognathia, bilateral cryptorchidism, hypospadias, abnormal fingers and toes, and severe developmental delay. FISH studies showed partial trisomy 7p resulting from a de novo unbalanced translocation. The application of molecular probes from the TWIST gene region (7p15.3-p21.1) and probes from the pseudoautosomal region (PAR) demonstrated that the 7p15.3-pter fragment was translocated onto Yp with the breakpoint within approximately 20 kb from the Yp telomere. We discuss the possible role of the TWIST gene in abnormal skull development and suggest that trisomy 7p cases with delayed closure of fontanels can be a result of TWIST gene dosage effect.

Abnormalities, Multiple↗
PubMed2001

Kabuki syndrome-like features associated with a small ring chromosome X and XIST gene expression.

Although clinical features in Kabuki syndrome (KS; Niikawa-Kuroki syndrome) have been well defined, the underlying genetic mechanism still remains unclear. We report a 9-year-old girl with typical KS-like facial appearance, skeletal and dermatoglyphic abnormalities, severe mental retardation, and growth deficiency. In 60 of 100 GTG-banded metaphases from peripheral blood lymphocytes, a ring chromosome smaller than a G group chromosome was found, which, according to reverse painting, consisted of Xq11.1q13. The proband's karyotype was described as mos45,X/46,X,+r(X). Several loci were analyzed with fluorescence in situ hybridization (FISH) and microsatellite markers revealing that one r(X) breakpoint mapped proximal to DXS422 (Xp11.21) and the second mapped distal to XIST gene, between loci DXS128E and DXS441 (Xq13.2). Uniparental disomy for X and r(X) was excluded and the paternal origin of r(X) was identified. XIST expression was demonstrated by nested reverse transcription polymerase chain reaction (RT-PCR) using primers spanning exons 5, 6i, and 6 in RNA prepared from lymphocytes. The observation of XIST expression is in contrast to two other cases in which the XIST gene was either not present on r(X) or not expressed. To our knowledge, this is the first case of Kabuki-like syndrome manifestations with r(X) and XIST expression.

Abnormalities, Multiple↗
PubMed2001

Construction of a detailed physical and transcript map of the candidate region for Russell-Silver syndrome on chromosome 17q23-q24.

Russell-Silver syndrome (RSS) is a heterogeneous disorder characterized mainly by pre- and postnatal growth retardation and characteristic dysmorphic features. The genetic cause of this syndrome is unknown. However, two autosomal translocations involving chromosome 17q25 were reported in association with RSS. Molecular analysis of the breakpoint on chromosome 17 of the de novo translocation previously described as t(1;17)(q31;q25) enabled us to refine the localization of the chromosome 17 breakpoint to 17q23-q24. Since no detailed mapping data were available for this region, we established a contig of yeast artificial chromosomes, P1 artificial chromosomes, bacterial artificial chromosomes, and cosmid clones for a 17q segment flanked by the sequence-tagged site (STS) markers D17S1557 and D17S940. This contig covers a physical distance of 4-5 Mb encompassing several novel markers. A transcript map was constructed by assigning genes and expressed sequence tags to the clone contig, and altogether 74 STS markers were mapped. Furthermore, the locus order and content provide insight into several duplication events that have occurred in the chromosomal region 17q23-q24. On the basis of our refined map, we have reduced the translocation breakpoint region to 65 kb between the newly derived markers 58T7 and CF20b. These data provide the molecular tools for the final identification of the RSS gene in 17q23-q24.

Abnormalities, Multiple↗
PubMed2001

Parental mosaicism of JAG1 mutations in families with Alagille syndrome.

The Alagille syndrome (AGS), a congenital disorder affecting liver, heart, skeleton and eye in association with a typical face, is an autosomal dominant disease with nearly complete penetrance and variable expression. AGS is caused by mutations in the developmentally important JAG1 gene. In our mutation screening, where 61 mutations in JAG1 were detected, we identified five cases where mosaicism is present. Our results point to a significant frequency of mosaicism for JAG1 mutations in AGS of more than 8.2%. Because mosaicism may be associated with a very mild phenotype, the appropriate diagnosis of AGS and consequently the determination of the recurrence risk can be complicated.

Alagille Syndrome↗
PubMed2000

Familial mosaicism of del(Y) and inv del(Y).

Molecular cytogenetic investigation of a male proband showing oligozoospermia (OAT I-II degrees ) has led to the detection of a Y-chromosome mosaicism. This mosaicism consists of a deleted Y chromosome with deletion of most of the long-arm heterochromatin, including the PAR2, del(Y), and a Y chromosome, which, in addition to that deletion, shows a paracentric long-arm inversion, inv del(Y), with breakpoints in the DAZ gene cluster in deletion interval 6 and within the remainder of the long-arm heterochromatin of the Y. The Y mosaicism is not confined to the sterile proband but is also detected in both his father and his fertile brother. Interestingly, the percentage of inv del(Y) is highest (80%) in the proband showing oligozoospermia.

Adult↗
PubMed1999

Maternal UPD 20 in a hyperactive child with severe growth retardation.

Maternal uniparental disomy was observed in a 4-year-old boy with severe pre- and postnatal growth retardation (body height: 85 cm = 12 cm < third percentile, head circumference: 48 cm = 10 cm < third percentile), a few minor facial findings, and with apparent hyperactivity. His intelligence is within the normal range for his age. Karyotype analysis revealed two cell lines, one apparently normal with 46,XY, the other with a tiny marker (47,XY, + mar). Microdissection and reverse chromosome painting using the marker DNA library as a probe, as well as PCR analysis revealed that the marker is from chromosome 20 and contains only the centromere and pericentromeric segments, but none of the pericentromeric loci for microsatellites. Microsatellite analysis of 25 chromosome 20 loci disclosed maternal uniparental disomy for all 16 informative markers. Maternal heterodisomy was evident for seven loci of the short arm segment 20p11.2-pter. Maternal isodisomy was found at five loci, three of them map to the proximal 20p11.2 segment and two to 20q. To our knowledge, this is the first case of maternal disomy 20 in humans.

Child Behavior Disorders↗
PubMed1998

Chromosome mapping of Rett syndrome: a likely candidate region on the telomere of Xq.

Rett syndrome (RS) is a disease of neurological development. First reported 30 years ago in 1966, its biological and genetic basis remains obscure. RS is commonly thought of as an X linked dominant disorder lethal to hemizygous males. The few familial cases would arise through mosaicism or because of occasional females failing to manifest the disorder through skewed X inactivation in relevant cell types. We have one family where the mother and daughter are affected with RS, and which can be explained according to this hypothesis. If the alternative proposal of Thomas (1996) is correct, that the lack of males affected by such disorders is the result of a high male to female ratio of germline mutations rather than of gestational lethality, then the RS gene should be located on the grandpaternal chromosome. Genomic screening with markers covering the whole X chromosome has been performed. Studies using multiple informative markers indicate that the RS locus is likely to be located close to one of the X chromosome telomeres. Further investigations in eight additional families suggest the most likely region for the RS gene to be is the distal part of Xq (Xq28).

Chromosome Mapping↗
PubMed1995

Localization of Alagille syndrome to 20p11.2-p12 by linkage analysis of a three-generation family.

Alagille syndrome (AGS) or arteriohepatic dysplasia is a rare but well-defined clinical entity that is usually inherited as an autosomal dominant trait. A limited number of patients carry a deletion in chromosome 20p, with 20p11.23-p12.2 as the area of minimal overlap. Recently, a family has been identified in which a balanced translocation with a breakpoint in 20p12 co-segregates with the AGS phenotype. Here, we report a three-generation family with AGS and in which the affected members have a normal karyotype. Linkage analysis was performed with markers from the 20p candidate region. A lod score of Z = 2.96 was obtained with D20S27 at no recombination. Combining D20S27 and D20S61 to a single highly informative locus resulted in a maximum lod score of Z = +3.56 at theta = 0.0. Haplotype analysis positioned AGS between D20S59 and D20S65, markers that define an interval of about 40 cM. Allelic loss was not observed for the tested markers and no abnormalities in the PAX1 candidate gene were detected. These findings demonstrate that the locus on chromosome 20p could be responsible for AGS in cytogenetically normal patients and argues for a general role of this locus in the aetiology of AGS.

Alagille Syndrome↗
PubMed1994

Molecular structure and chromosomal mapping of the human homolog of the agouti gene.

The agouti (a) locus in mouse chromosome 2 normally regulates coat color pigmentation. The mouse agouti gene was recently cloned and shown to encode a distinctive 131-amino acid protein with a consensus signal peptide. Here we describe the cloning of the human homolog of the mouse agouti gene using an interspecies DNA-hybridization approach. Sequence analysis revealed that the coding region of the human agouti gene is 85% identical to the mouse gene and has the potential to encode a protein of 132 amino acids with a consensus signal peptide. Chromosomal assignment using somatic-cell-hybrid mapping panels and fluorescence in situ hybridization demonstrated that the human agouti gene maps to chromosome band 20q11.2. This result revealed that the human agouti gene is closely linked to several traits, including a locus called MODY (for maturity onset diabetes of the young) and another region that is associated with the development of myeloid leukemia. Initial expression studies with RNA from several adult human tissues showed that the human agouti gene is expressed in adipose tissue and testis.

Agouti Signaling Protein↗
PubMed1994

The gene for the amyloid precursor-like protein APLP2 is assigned to human chromosome 11q23-q25.

The human amyloid precursor-like protein APLP2 is a highly conserved homologue of a sequence-specific DNA-binding mouse protein with a predicted function in the cell cycle. Somatic cell hybrids segregating human chromosomes were used to assign the APLP2 gene to chromosome 11. Fluorescence in situ hybridization confirmed this assignment and further localized the gene to q23-q25.

Amyloid beta-Protein Precursor↗
PubMed1994

Interstitial deletion of 22q11 in DiGeorge syndrome detected by high resolution and molecular analysis.

Two patients with DiGeorge syndrome (DGS), one with and one without characteristic dysmorphic facial features, were studied by high resolution banding, fluorescence in situ hybridization (FISH) and quantitative Southern blotting. In both patients, even in the one with no typical facial stigmata, a microdeletion within 22q11.2 was detected. FISH analysis, in particular, is most useful in screening for 22q11.2 segmental monosomy in patients with DGS and DGS-related features.

Blotting, Southern↗