Trisomy 10p due to a de novo t(10p;13p)

Summary A new case of trisomy 10p has been identified by means of the GTG-banding technique. The patient is a female child carrying a sporadic translocation, t(10;13)(p11;p11), and affected by microsomatia and microcephaly with facial dysmorphia, retarded growth, weight gain, and psychomotor development, and bilateral talipes.     

Partial trisomy 6p due to familial translocation t(6;20)(p21;p13)

Summary Cytogenetic findings in a case of partial trisomy 6p due to a translocation t(6;20)(p21;p13) and eleven balanced translocation heterozygotes are described.The clinical data of the proposita are compared with those of five other published cases. A partial trisomy 6p syndrome is postulated, characterized by: low birth weight, psychomotor retardation, craniofacial abnormalities (such as high prominent forehead, large fontanel, wide sagittal suture, blepharoptosis, low-set and/or malformed ears), congenital heart malformation, small kidneys, and proteinuria. Linkage studies have shown that the breakpoint in chromosome 6 involved in this translocation is close to the HLA gene cluster.     

Sperm chromosome analysis of two males heterozygous for a t(2;17)(q35;p13) and t(3;8)(p13;p21) reciprocal translocation

Summary Sperm chromosome complements from two males, one heterozygous for the reciprocal translocation t(2;17)(q35;p13) (n = 18) and one for t(3;8) (p13;p21) (n = 73), were analyzed. Only 2:2 segregations were observed with t(2;17): alternate, 56%; adjacent-I, 33%; adjacent-II, 11%. Both 2:2 and 3:1 meiotic segregations occurred in t(3;8): alternate, 34.2%; adjacent-I, 43.8%; adjacent-II, 20.5% and 3:1, 1.4%. A significant excess of chromosomally normal versus balanced sperm complements was observed with both translocation heterozygotes. The frequencies of other chromosome aberrations unrelated to the translocations were 16.7% for t(2;17) and 8.2% for t(3;8). The ratio of X-bearing to Y-bearing sperm was not different from the theoretically expected ratio of 1:1.     

Mosaic 13 trisomy due to de novo 13/13 translocation with subsequent fission karyotype: 46,XX,-13,+t(13;13)(p11;q11)/46,XX,del(13)(p11)

Summary A severely retarded child with multiple malformations was found to present a mosaic karyotype 46,XX,-13,+t(13;13)(p11;q11)/46,XX,del (13)(p11), which probably originated as the result of a de novo 13/13 translocation in a parental gamete, followed by postzygotic fission of the translocation chromosomse.     

Partial trisomy 13 as a result of de novo (6p;13q) translocation

Summary A newborn infant with the clinical features of the Patau syndrome was found to have excess chromosome 13 material present as a tandem translocation involving the short arm of chromosome 6 and the long arm of an extra chromosome 13: 46,XY,t(6;13)(p24;q12). The major part of the long arm of the extra chromosome 13 was attached linearly (tandem translocation) to the short arm of chromosome 6. Both parents were phenotypically and karyotypically normal.     

Mosaic 13 trisomy due to de novo 13/13 translocation with subsequent fission. Karyotype: 46,XX,-13, +t(13;13)(p11;q11)/46,XX,del(13)(p11). A second example

In this paper we report a second example of 13 trisomy mosaicism due to de novo 13/13 translocation followed by postzygotic fission of the translocation chromosome in a polymalformed female newborn.     

Partial trisomy 8p (8p11.2-->pTER) and deletion of 13q (13q32-->qTER): case report

We report a female infant with partial trisomy 8p (8p11.2-->pter) and deletion of 13q (13q32-->qter). She was born with mild hypotonia, intrauterine growth retardation, microcephaly, micrognathia, large low set ears, pectus excavatum, anteriorly placed anus, and bilateral clinodactyly. Echocardiography showed left ventricular hypertrophy, bicuspid aortic valve, dilatation of the aorta and pulmonary artery, and prolapse of atrio-venticular valve leaflets. Cytogenetic investigation of her sister and her father showed that the altered region resulted from a balanced translocation between the part of the long arm of chromosome 13 and short arm of chromosome 8. In partial trisomy 8p, the clinical picture of the patients comprises hypotonia, structural brain abnormalities, facial anomalies including a large mouth with a thin upper lip, a high arched palate, a broad nasal bridge, an abnormal maxilla or mandible, malformed, low set ears, and orthopedic anomalies. Although patients with proximal deletions of 13q that do not extend into band q32 have mild to moderate mental and growth delays with variable minor anomalies, patients with more distal deletions including at least part of band q32 usually have major malformations such as retinoblastoma, mental-motor growth retardation, malformation of brain and heart, anal atresia, and anomalies of the face and limbs. To our knowledge partial trisomy 8p and partial monosomy of 13q have not been reported previously in the same person.     

Trisomy 9p due to paternal translocation, t(9;13) (q13;q12).

A 16-year-old girl with trisomy 9p is described. She had a short stature, severe mental retardation and the following abnormal clinical findings: peculiar face with hypertelorism, downward slanting palpebral fissures, convergent strabismus, a bulbous nose with broad and prominent bridge, short upper lip, narrow, high-arched palate; short neck with low hairline; severe kyphoscoliosis and a congenital clubfoot deformity; hypoplasia and dysplasia of several phalanges of the fingers and toes and some nails, a delay by about 6 years in bone age, and remarkable dermatoglyphic patterns. The father and 3 other family members carried a balanced translocation between chromosomes 9 and 13, t(9;13)(q13;q12).     

2 cases of partial trisomy 10p due to a paternal translocation t(10p;18)(p13;q23)]

Two brothers trisomic for the distal two thirds of 10p are reported. Trisomy results from the malsegregation of a familial translocation rcp (10;18)(p13;q23) present in the father, a half-brother and the grand-father of the propositi. The phenotype is comparable to that of other 10p trisomic patients reported in the literature.     

p13 protects against Parkinson's disease

Mitochondrial dysfunction is thought to contribute to Parkinson's disease progression, and factors that can overcome mitochondrial defects could potentially be used to combat the disease and prevent neuronal death. In this issue, Inoue et al 1 report that reduction of p13, a mitochondrial protein that inhibits complex I assembly, rescues the cellular and behavioral defects of Parkinson's disease models. This work suggests that stabilizing the mitochondrial electron transport chain may be beneficial in the context of Parkinson's disease.     

Interstitial deletion (2)(p13p15)

Summary A dysmorphic 5-year-old girl with severe growth and mental deficiency was studied. She presented a de novo interstitial 2p deletion. Karyotype: 46,XX,del(2)(p13p15).     

Tiling resolution array CGH of dic(7;9)(p11 approximately 13;p11 approximately 13) in B-cell precursor acute lymphoblastic leukemia reveals clustered breakpoints at 7p11.2 approximately 12.1 and 9p13.1

The dic(7;9)(p11 approximately 13;p11 approximately 13) is a recurrent chromosomal abnormality in acute lymphoblastic leukemia (ALL), mainly of B-lineage. Although more than 20 dic(7;9)-positive ALLs have been reported to date, the molecular genetic consequences of this aberration are unknown. We performed tiling resolution (32K) genome-wide array-based comparative genomic hybridization (array CGH) analysis of three cases with dic(7;9) in order to characterize the breakpoints on 7p and 9p. The analysis showed a clustering of breakpoints within 9p13.1 in all three cases and within 7p11.2 in two cases; the array CGH revealed two different breakpoints - 7p12.1 and 7p14.1 - in the remaining case. Based on these findings the abnormality should hence be designated dic(7;9)(p11.2 approximately 12.1;p13.1). Locus-specific fluorescence in situhybridization analysis of one of the cases narrowed down the 7p11.2 breakpoint to a <500-kb segment in this sub-band, a region containing three known genes. Unfortunately, lack of material precluded further molecular genetic studies, and it thus remains unknown whether the pathogenetically important outcome of the dic(7;9) is formation of a chimeric gene or loss of 7p and/or 9p material.     

De novo t(2;13)(p24.3;q14.2) and retinoblastoma

Summary The two probes H3-8 and H2-42, known to be located in 13q14, were mapped by in situ hybridization to either side of the 13 breakpoint of an apparently balanced de novo t(2;13)(p24.3;q14.2) detected in a patient with retinoblastoma as the only phenotypic manifestation.     

Familial reciprocal translocation t(9;13)(p11;p12) investigated by silver staining and in situ hybridisation

Summary A maternal de novo reciprocal translocation between the short arms of chromosomes 9 and 13 is reported. Using C-, Q- or G-banding, it was not possible to determine the precise breakpoint on 13, but a combination of silver staining and in situ hybridisation was used to do so on the two chromosomes, and it was demonstrated that the break on chromosome 13 had occurred within the NOR.     

Trisomy 9p in a girl whose mother has a translocation t(9;20)(q12;p13)

Summary R banding of the fine structure of the chromatids has enabled us to study a new case of trisomy for the short arm of chromosome 9. The syndrome+9p was due to nondisjunction of a maternal translocation t(9;20)(q12;p13).     

Sequential Loading of Saccharomyces cerevisiae Ku and Cdc13p to Telomeres

Ku is a heterodimeric protein involved in nonhomologous end-joining of the DNA double-stranded break repair pathway. It binds to the double-stranded DNA ends and then activates a series of repair enzymes that join the broken DNA. In addition to its function in DNA repair, the yeast Saccharomyces cerevisiae Ku (Yku) is also a component of telomere protein-DNA complexes that affect telomere function. The yeast telomeres are composed of duplex C_1–3(A/T)G_1–3 telomeric DNA repeats plus single-stranded TG_1–3 telomeric DNA tails. Here we show that Yku is capable of binding to a tailed-duplex DNA formed by telomeric DNA that mimics the structure of telomeres. Addition of Cdc13p, a single-stranded telomeric DNA-binding protein, to the Yku-DNA complex enables the formation of a ternary complex with Cdc13p binding to the single-stranded tail of the DNA substrate. Because pre-loading of Cdc13p to the single-stranded telomeric tail inhibits the binding of Yku, the results suggested that loading of Yku and Cdc13p to telomeres is sequential. Through generating a double-stranded break near telomeric DNA sequences, we found that Ku protein appears to bind to the de novo synthesized telomeres earlier than that of Cdc13p in vivo. Thus, our results indicated that Yku interacts directly with telomeres and that sequential loading of Yku followed by Cdc13p to telomeres is required for both proteins to form a ternary complex on telomeres. Our results also offer a mechanism that the binding of Cdc13p to telomeres might prevent Yku from initiating DNA double-stranded break repair pathway on telomeres.DNA damages in the form of double-stranded breaks (DSBs)⁴ compromise the integrity of genomes. Failure in repairing or mis-repairing double-stranded breaks can lead to chromosome instability and eventually cell death or cancer (1). Double-stranded breaks are repaired by two main pathways, the homologous recombination and nonhomologous DNA end-joining. In nonhomologous DNA end-joining, Ku is the first protein to bind to the DNA ends to initiate the repair pathway (2). Upon binding, Ku then recruits a series of repair enzymes to join the broken ends (2). Ku is a heterodimeric protein composed of 70- and ∼80-kDa subunits. In Saccharomyces cerevisiae, Ku includes Yku70 and Yku80 subunits. Because the biochemical configuration of the broken ends could be very diverse on DSBs, Ku binds to double-stranded ends in a sequence- and energy-independent manner. It is capable of binding to DNA ends with blunt 3′-overhangs or 5′-overhangs as well as double-stranded DNA with nicks, gaps, or internal loops (3–7). However, Ku does not have high affinity to single-stranded DNA. The crystal structure of human Ku heterodimer indicates that it forms a ring structure that encircles duplex DNA (7). This unique structure feature enables Ku to recognize DNA ends and achieves its high affinity binding.In additional to the role in double-stranded break repair, Ku was shown to be a component of telomeric protein-DNA complex in yeast and mammals (8–10). Telomeres are terminal structures of chromosomes composed of short tandem repeated sequences (11, 12). Mutation of YKU70 or YKU80 causes defects in telomere structure (13–15), telomere silencing (16–19), and replication timing of telomeres (20). The function of yeast Ku (Yku) on telomeres could mediate through protein-protein interaction with Sir4p or protein-RNA interaction with Tlc1 RNA (21, 22). For example, through the interaction with Sir4p, Yku selectively affects telomeres silencing but not the silent mating type loci (17). Yku could also bind to telomerase Tlc1 RNA for telomere length maintenance (22). Judged by the DNA binding activity of Yku, it is reasonable to suggest that it may bind directly to telomeric DNA. Indeed, it was shown that human Ku is capable of binding directly to telomeric DNA in vitro (15). Moreover, because the deletion of SIR4 in budding yeast (23) or Taz1 in fission yeast (24) does not abolish the association of Ku with chromosomal ends, this suggests that Ku might bind directly to telomeric DNA in cells. However, because yeast telomeres have a short 12–14-mer single-stranded tail (25), it is uncertain whether Yku could pass the single-stranded region to reach its binding site. The direct binding of Yku to telomeric DNA has not been experimentally determined.In contrast to double-stranded breaks, the ends of linear chromosomes are not recognized by repair enzymes as DNA damage. In S. cerevisiae, Cdc13p is the single-stranded TG_1–3 DNA-binding protein that enables cells to differentiate whether the ends of a linear DNA are telomeres or broken ends (26–29). Thus, although the mechanism of how cells prevent the activation of DSB repair pathway in telomere is unclear, it is likely that binding of Cdc13p to telomeres might inhibit the initiation of DNA damage response by the Ku protein. Here, using a tailed-duplex DNA synthesized by telomeric DNA sequences to mimic telomere structure, we showed that Yku binds directly to this tailed-duplex DNA substrate and forms a ternary complex with Cdc13p. Our results also showed that Yku loaded to a de novo synthesized telomere earlier than Cdc13p in vivo. These results support the direct binding of Yku to telomeric DNA and that the spatial orientation of Cdc13p might block the activation of DSB repair pathway on telomeres.