Proximal Long Arm Of Chromosome Research Articles

Deletion of the MBII-85 snoRNA Gene Cluster in Mice Results in Postnatal Growth Retardation

Prader-Willi syndrome (PWS [MIM 176270]) is a neurogenetic disorder characterized by decreased fetal activity, muscular hypotonia, failure to thrive, short stature, obesity, mental retardation, and hypogonadotropic hypogonadism. It is caused by the loss of function of one or more imprinted, paternally expressed genes on the proximal long arm of chromosome 15. Several potential PWS mouse models involving the orthologous region on chromosome 7C exist. Based on the analysis of deletions in the mouse and gene expression in PWS patients with chromosomal translocations, a critical region (PWScr) for neonatal lethality, failure to thrive, and growth retardation was narrowed to the locus containing a cluster of neuronally expressed MBII-85 small nucleolar RNA (snoRNA) genes. Here, we report the deletion of PWScr. Mice carrying the maternally inherited allele (PWScrm−/p+) are indistinguishable from wild-type littermates. All those with the paternally inherited allele (PWScrm+/p−) consistently display postnatal growth retardation, with about 15% postnatal lethality in C57BL/6, but not FVB/N crosses. This is the first example in a multicellular organism of genetic deletion of a C/D box snoRNA gene resulting in a pronounced phenotype.

Patient with novel interstitial deletion of chromosome 3q13.1q13.3 and agenesis of the corpus callosum

Interstitial deletions of the proximal long arm of chromosome 3 are rare. Only eight previously reported patients have deletions involving the proximal segment of 3q. Of these patients, three had agenesis of the corpus callosum and one had holoprosencephaly. We report here a patient with a small unique interstitial deletion of the long arm of chromosome 3 spanning 3q13.1q13.3. This patient has agenesis of the corpus callosum, global developmental delay, and distinctive facial features of a small nose, anteverted nares, and broad nasal root. Our patient provides further evidence that a gene involved in corpus callosum development or neuronal migration may reside in this region.

Clinical, cytogenetic, and molecular genetic characterization of two unrelated patients with different duplications of 21q

We present 2 patients with dup(21q). Patient MP01 had mild mental retardation, facial findings characteristic of Down syndrome (DS), and a terminal duplication of chromosome 21. His karyotype was 46,XY,dup(21) (q22.1-qter). Patient MP03 had mild mental retardation, minor anomalies not characteristic of DS, and a duplication of the proximal long arm of chromosome 21, karyotype 46,XX,dup(21) (q11.2-q21.2). The patients were studied with single-copy DNA sequences from 20 loci on chromosome 21 to characterize the extent of the duplicated regions at the DNA level. DNA loci from D21S55 to COL6A1 were triplicated in patient MP01 while loci from D21S13 to D21S8 were triplicated in patient MP03. Our results support the hypothesis of a critical region of chromosome 21, which in triplicate is responsible for many of the facial changes associated with DS. Other genes outside this region may also contribute to other abnormalities observed in DS.

An interstitial deletion of chromosome 7 at band q21: A case report and review

We report on a girl with moderate developmental delay and mild dysmorphic features. Cytogenetic investigations revealed a de novo interstitial deletion at the proximal dark band on the long arm of chromosome 7 (7q21.1-q21.3) in all analyzed G-banded metaphases of lymphocytes and fibroblasts. Fluorescence in situ hybridization (FISH) and molecular studies defined the breakpoints at 7q21.11 and 7q21.3 on the paternal chromosome 7, with the proximal deletion breakpoint between the elastin gene (localized at 7q11.23) and D7S2517, and the distal breakpoint between D7S652 and the COL1A2 gene (localized at 7q21.3-q22.1). Deletions of interstitial segments at the proximal long arm of chromosome 7 at q21 are relatively rare. The karyotype-phenotype correlation of these patients is reviewed and discussed. The clinical findings of patients with a deletion at 7q21 significantly overlap with those of patients with maternal uniparental disomy of chromosome 7 (matUPD(7)) and Silver-Russell syndrome (SRS, OMIM 180860). Therefore, 7q21 might be considered a candidate chromosomal region for matUPD(7) and SRS.

Recurrent adjacent‐2 segregation of a familial t(14;21)(q11.2;q11.2): Phenotypic comparison of two brothers and a paternal aunt inheriting the der(14)

A 14-year-old boy was referred for a genetics evaluation after high-resolution chromosome analysis showed a small amount of extra material in the proximal long arm of chromosome 21. Five years prior, his karyotype analysis was interpreted as normal with a variant chromosome 21. The patient has short palpebral fissures, strabismus, flat antihelices of the ears, long thumbs with bilaterally absent interphalangeal creases, proximal bilateral 3/4 syndactyly, small testes, hypotonia, mental retardation, and speech problems. He has significant depression and behavioral problems including hyperactivity, aggression, and impulsivity. His 8-year-old brother has more severe behavioral disturbances and depression, but less significant mental retardation. A paternal aunt has mental retardation, is unusually docile, and appears similar to our patient. Chromosome analysis and fluorescence in situ hybridization (FISH) whole chromosome paint of chromosome 21 showed that the patient's father carries a "cryptic" balanced translocation, 46,XY, t(14;21)(q11.2;q11.2), as does the patient's paternal grandmother. Uniparental disomy studies using seven informative polymorphic nucleotide repeat markers from 14q and 21q confirmed biparental inheritance of the number 14 and 21 chromosomes for each brother, and indicate that they and the paternal aunt, all of whom inherited the der(14), are monosomic for proximal 21q and trisomic for proximal 14q. These karyotypes arose through an adjacent-2 segregation in the father on two occasions, and from the paternal grandmother on one occasion. This family is an example of recurrent malsegregation with translocations involving the acrocentrics.

Williams-Beuren syndrome: a challenge for genotype-phenotype correlations.

Many human chromosomal abnormality syndromes include specific cognitive and behavioural components. Children with Prader-Willi syndrome lack a paternally derived copy of the proximal long arm of chromosome 15, and eat uncontrollably; in Angelman syndrome lack of a maternal contribution of 15q11-q13 results in absence of speech, frequent smiling and episodes of paroxysmal laughter; deletions on 22q11 can be associated with obsessive behaviour and schizophrenia. The neurodevelopmental disorder Williams-Beuren syndrome (WBS), is caused by a microdeletion at 7q11.23 and provides us with one of the most convincing models of a relationship that links genes with human cognition and behaviour. The hypothesis is that deletion of one or a series of genes causes neurodevelopmental abnormalities that manifest as the fractionation of mental abilities typical of WBS. Detailed molecular characterization of the deletion alongside well-defined cognitive profiling in WBS provides a unique opportunity to investigate the neuromolecular basis of complex cognitive behaviour, and develop integrated approaches to study gene function and genotype-phenotype correlations.

A study of cryptic terminal chromosome rearrangements in recurrent miscarriage couples detects unsuspected acrocentric pericentromeric abnormalities.

Fifty chromosomally normal couples with three or more miscarriages were examined using fluorescent in situ hybridisation (FISH) and a library of subtelomere-specific probes together with alphoid repeats mapping to the acrocentric centromeres. Six abnormalities were found. Firstly, a cryptic reciprocal subtelomere translocation between the long arm of a chromosome 3 and the short arm of a chromosome 10. The other five cryptic abnormalities involved the acrocentric chromosome pericentromeric regions and in one case also Yp. Two patients had a rearranged chromosome 13, where the centromeric region was found to be derived from the short arm, centromere and proximal long arm of chromosome 15. Another two patients had a derived chromosome 22, where the centromere was replaced by two other centromeres, one derived from chromosome 14 and the other from either chromosome 13 or 21, while one patient had the subtelomere region of Yp translocated onto the short arm of a chromosome 21. These abnormalities may be the underlying cause of the recurrent miscarriages, because they may result in abnormal pairing configurations at meiosis leading to non-disjunction of whole chromosomes at metaphase I. The frequency of rearrangements seen in the recurrent miscarriage patient population was significantly different from that in the control group ( P=0.0096, Fisher's exact test) due to the acrocentric pericentromeric abnormalities.

Primary effusion lymphomas exhibit complex and recurrent cytogenetic abnormalities.

Cytogenetic findings in a few primary effusion lymphoma (PEL) cell lines have been reported, but only three complete karyotypes of primary specimens from patients with this neoplasm have been published. In this study, cytogenetic analysis was performed on 11 effusion specimens from 10 patients with PEL. We corroborate data obtained from the cell line studies that trisomy 7, trisomy 12 and aberrations in the proximal long arm of chromosome 1 (1q) are recurring cytogenetic aberrations in PEL and also identify breakpoints at 3q23, 7p22, 7q22, 10q24, 12q24, 13q22, 14q24, 14q32, 15p11.2 and Xq22 as well as +8, +15, +19, +X and -Y as recurring chromosome abnormalities. The identification of recurring cytogenetic aberrations may lead to delineation of the genetic events in PEL.

Tandem duplication of bands g13.13g13.33 resulting in partial trisomy of long arm of chromosome 19

A tandem duplication of the proximal long arm of chromosome 19 was identified in a 2 year old female infant with developmental delays. GTG technique revealed that the long arm region 19q13.13-q13.33 was tandemly duplicated. The karyotype is: 46,XX,dup(19)(q13.13q13.33) FISH technique using whole chromosome paint showed that the abnormal chromosome was composed entirely of chromosome 19 material. Parental chromosomes were normal.To our knowledge, this is the first case of “pure” trisomy of 19q13.13-q13.33. Clinical follow up of our patient and a further molecular characterization of the breakpoints involved should shed light on the development effects of the duplicated genes in this region. These studies are in progress.

Obsessive-Compulsive Symptoms in Prader-Willi and “Prader-Willi—Like” Patients

To compare obsessive-compulsive (OC) symptoms in patients with Prader-Willi syndrome (PWS) and symptoms in a group of patients presenting with "Prader-Willi-like" features but without the genetic abnormalities associated with PWS. 16 patients aged 4 through 20 years were evaluated in a clinic specializing in the assessment and management of behavioral and food-related problems in PWS. Eight patients were found to have key features of the syndrome but did not have a PWS genotype. These PWS-like subjects were matched to 8 clinic patients with a confirmed deletion of the PWS critical region of the paternally derived chromosome 15. All subjects were evaluated for obesity, IQ, food-related problems, maladaptive behaviors, and non-food-related OC symptoms. There were no differences between the 2 groups with respect to measures of obesity, IQ, food-related difficulties, or overall maladaptive behaviors. The PWS group showed significantly greater numbers of OC symptoms and greater symptom severity. Patients with PWS have elevated numbers of OC symptoms and significant symptom-related impairment which are not explained by developmental delay, food-related difficulties, or obesity. OC symptoms are part of a behavioral phenotype that accompanies deletions on the proximal long arm of chromosome 15 in PWS.

Maternal disomy and Prader-Willi syndrome consistent with gamete complementation in a case of familial translocation (3;15) (p25;q11.2)

Maternal uniparental disomy (UPD) for chromosome 15 is responsible for an estimated 30% of cases of Prader-Willi syndrome (PWS). We report on an unusual case of maternal disomy 15 in PWS that is most consistent with adjacent-1 segregation of a paternal t(3;15)(p25;q11.2) with simultaneous maternal meiotic nondisjunction for chromosome 15. The patient (J.B.), a 17-year-old white male with PWS, was found to have 47 chromosomes with a supernumerary, paternal der(15) consisting of the short arm and the proximal long arm of chromosome 15, and distal chromosome arm 3p. The t(3;15) was present in the balanced state in the patient's father and a sister. Fluorescent in situ hybridization analysis demonstrated that the PWS critical region resided on the derivative chromosome 3 and that there was no deletion of the PWS region on the normal pair of 15s present in J.B. Methylation analysis at exon alpha of the small nuclear ribonucleoprotein-associated polypeptide N (SNRPN) gene showed a pattern characteristic of only the maternal chromosome 15 in J.B. Maternal disomy was confirmed by polymerase chain reaction analysis of microsatellite repeats at the gamma-aminobutyric acid receptor beta3 subunit (GABRB3) locus. A niece (B.B.) with 45 chromosomes and the derivative 3 but without the der(15) demonstrated a phenotype consistent with that reported for haploinsufficiency of distal 3 p. Uniparental disomy associated with unbalanced segregation of non-Robertsonian translocations has been reported previously but has not, to our knowledge, been observed in a case of PWS. Furthermore, our findings are best interpreted as true gamete complementation resulting in maternal UPD 15 and PWS.

A Gene for Autosomal Dominant Hypohidrotic Ectodermal Dysplasia ( EDA3) Maps to Chromosome 2q11-q13

Autosomal dominant hypohidrotic ectodermal dysplasia (ADHED) is a disorder characterized by fine, slow-growing scalp and body hair, sparse eyebrows and eyelashes, decreased sweating, hypodontia, and nail anomalies. By genetic linkage analysis of a large ADHED kindred, we have mapped a gene for ADHED (EDA3) to the proximal long arm of chromosome 2 (q11-q13). Obligate recombinations localize EDA3 to an approximately 9-cM interval between D2S1321 and D2S308, with no apparent recombinations with markers D2S1343, D2S436, D2S293, D2S1894, D2S1784, D2S1890, D2S274, and CHLC.GAAT11C03.

Prader-Willi syndrome: relationship of adiposity to plasma leptin levels.

Prader-Willi syndrome (PWS) is an autosomal dominant disorder involving the proximal long arm of chromosome 15, in which obesity is common. However, there is limited information on the underlying physiological mechanisms promoting obesity in this population. We tested whether there was a significant positive association between leptin and total body fat (TBF) in subjects with PWS, and whether this association was stronger among subjects with than without PWS. We studied 21 PWS patients and 64 non-PWS controls on whom we measured serum leptin, total body fat, glucose, insulin, and resting energy expenditure. We tested whether the slope of the regression line between leptin and TBF (in kg), measured by dual energy X-ray absorptiometry, was the same for PWS patients and non-PWS controls. Regression analyses indicated that the leptin-TBF association was significantly stronger among PWS patients. In contrast, the slope of the leptin-body mass index association did not significantly differ between PWS patients and non-PWS controls. None of the other outcome variables showed associations with leptin. Results suggest that the role of leptin in promoting obesity may be greater among subjects with PWS than among non-PWS controls.

Metastatic sublines of an SV40 large T antigen immortalized human prostate epithelial cell line.

The available human prostate cancer cell lines that are metastatic in athymic nude mice all have complex, highly aneuploid karyotypes. Other prostatic cells immortalized by transforming genes of SV40 or HPV and converted to tumorigenicity by additional genetic manipulation are not reported to be metastatic. Tumorigenic sublines of human prostate epithelial cells previously immortalized by transfection with the SV40T antigen gene were obtained by sequential passage in male athymic nude mice. These sublines were evaluated histopathologically for tumorigenicity and metastasis in athymic nude mice after subcutaneous, intraperitoneal, and intraprostatic injection. Each subline was characterized by standard (GTG-banding) cytogenetic and FISH analysis, and RNase protection assays for androgen receptor expression. Two sublines produced metastases in lungs and the diaphragm of most mice after either intraprostatic or intraperitoneal injection. The M2205 subline formed large local tumors after intraprostatic injection. Cytogenetic aberrations present in the metastatic sublines, but not in the tumorigenic, nonmetastatic lines or the parental P69SV40T line, included dup(11)(q14q22), der(16) t (16;19) (q24;q13.1), which resulted in the loss of the short arm and proximal long arm of chromosome 19 (19q13.1-->19pter), and loss of the Y chromosome. None of the sublines expressed the androgen receptor. These cytogenetically defined, SV40T-immortalized human prostate epithelial cell lines, with distinct biological behaviors in vivo, provide additional tools for the genetic analysis of the emergence of metastatic capacity.

Inherited Interstitial Duplications of Proximal 15q: Genotype-Phenotype Correlations

We present the cytogenetic, molecular cytogenetic, and molecular genetic results on 20 unrelated patients with an interstitial duplication of the proximal long arm of chromosome 15. Multiple probes showed that the Prader-Willi/Angelman critical region (PWACR) was included in the duplication in 4/20 patients, each ascertained with developmental delay. The duplication was also found in two affected but not in three unaffected sibs of one of these patients. All four probands had inherited their duplication from their mothers, three of whom were also affected. Two of the affected mothers also carried a maternally inherited duplication, whereas the duplication in the unaffected mother and in an unaffected grandmother was paternal in origin, raising the possibility of a parental-origin effect. The PWACR was not duplicated in the remaining 16 patients, of whom 4 were referred with developmental delay. In the 14 families for which parental samples were available, the duplication was inherited with equal frequency from a phenotypically normal parent, mother or father. Comparative genomic hybridization undertaken on two patients suggested that proximal 15q outside the PWACR was the origin of the duplicated material. The use of PWACR probes discriminates between a large group of duplications of no apparent clinical significance and a smaller group, in which a maternally derived PWACR duplication is consistently associated with developmental delay and speech difficulties but not with overt features of either Prader-Willi syndrome or Angelman syndrome.

The genetic basis for Prader-Willi syndrome: the importance of imprinted genes.

The genetic basis of Prader-Willi syndrome involves imprinted genes on the proximal long arm of chromosome 15. The basic defect appears to be the absence of function of genes that are normally expressed in a monoallelic fashion only from the paternal chromosome. In 60-70% of patients with Prader-Willi syndrome, the genetic defect is a deletion in the area of 15q11-13 on the paternal chromosome. A further 25-30% of patients with Prader-Willi syndrome do not have paternal deletions, the defect being due to uniparental disomy (UPD) for maternal chromosome 15. Paternal deletions and maternal UPD are functionally equivalent, as they both result in the absence of a paternal contribution to the genome in the 15q11-13 region. The SNRPN (small nuclear ribonucleoprotein-associated polypeptide N) gene has a critical role in the 15q11-13 region, as it is probably part of the putative imprinting centre that regulates the expression of several genes in the Prader-Willi syndrome transcriptional domain. Two further rare causes of Prader-Willi syndrome are imprinting mutations, which are microdeletions or point mutations in the putative imprinting control region, and translocations with their breakpoints in the Prader-Willi syndrome region.

Familial transmission of a deletion of chromosome 21 derived from a translocation between chromosome 21 and an inverted chromosome 22

Chromosome analysis of a newborn boy with Down syndrome resulted in the identification of a family with an unusual derivative chromosome 22. The child has 46 chromosomes, including two chromosomes 21, one normal chromosome 22, and a derivative chromosome 22. Giemsa banding and fluorescent in situ hybridization (FISH) studies show that the derivative chromosome is chromosome 22 with evidence of both paracentric and pericentric inversions, joined to the long arm of chromosome 21 from 21q21.2 to qter. The rearrangement results in partial trisomy 21 extending from 21q21.2 to 21q terminus in the patient. The child's mother, brother, maternal aunt, and maternal grandmother are all carriers of the derivative chromosome. All have 45 chromosomes, with one normal chromosome 21, one normal chromosome 22, and the derivative chromosome 22. The rearrangement results in the absence of the short arm, the centromere, and the proximal long arm of chromosome 21 (del 21pter-21q21.2) in carriers. Carriers of the derivative chromosome in this family have normal physical appearance, mild learning disabilities and poor social adjustment.

Lysinuric Protein Intolerance (LPI) Gene Maps to the Long Arm of Chromosome 14

Lysinuric protein intolerance (LPI) is an autosomal recessive disease characterized by defective transport of cationic amino acids and by hyperammonemia. Linkage analysis in 20 Finnish LPI families assigned the LPI gene locus to the proximal long arm of chromosome 14. Recombinations placed the locus between framework markers D14S72 and MYH7, a 10-cM interval in which the markers D14S742, D14S50, D14S283, and TCRA showed no recombinations with the phenotype. The phenotype was in highly significant linkage disequilibrium with markers D14S50, D14S283, and TCRA. The strongest allelic association obtained with marker TCRA, resulting in a P(excess) value of .98, suggests that the LPI gene locus lies in close proximity to this marker, probably within a distance of < 100 kb.

MR of the pituitary in patients with Prader-Willi syndrome: size determination and imaging findings.

Prader-Willi syndrome (PWS) is an unusual genetic disorder characterized by short stature, obesity, hypogonadism, hypotonia, cognitive impairment, and dysmorphic facies. There is an interstitial deletion of the proximal long arm of chromosome 15 in about 70 % of patients. Some of these clinical features suggest a central hypothalamic/pituitary dysfunction, and recent investigations have demonstrated a marked impairment in spontaneous growth hormone (GH) secretion. We studied 15 GH-deficient PWS patients by magnetic resonance imaging (MRI) to determine whether there was a diminution in the gross morphological size of the anterior pituitary gland, the site of GH synthesis. We also set out to catalog the pertinent imaging findings in this patient population. Our results indicate that this is the first report documenting pituitary size by MRI in PWS patients. No statistically significant difference was found in the height of the anterior pituitary gland in PWS patients compared with either normal children or children with isolated GH deficiency. An interesting imaging finding is that three of 15 patients (20 %) demonstrated complete absence of the posterior pituitary bright spot (PPBS), and a fourth patient demonstrated a small PPBS. These observations reflect an objective physiologic disturbance in the hypothalamus. The clinical and radiologic implications of these findings are discussed.

A human SHC-related sequence maps to chromosome 17, the SHC gene maps to chromosome 1.

The SHC gene encodes a protein that is thought to act as an adapter in many signal transduction pathways; the SHC protein probably facilitates the activation of RAS proteins in response to a variety of factors. We have mapped the human SHC gene and have identified a new SHC-related sequence. We have sequenced the region corresponding to the SHC 3' UTR from both loci and have mapped cosmids by fluorescence in situ hybridization. The human SHC gene maps to the proximal long arm of chromosome 1 and the SHC-related sequence maps to the proximal long arm of chromosome 17. A number of cancers have been positioned in the proximal long arm of chromosome 1; this is of interest given the oncogenic potential of the SHC protein.