Deletion of the Telomerase Reverse Transcriptase Gene and Haploinsufficiency of Telomere Maintenance in Cri du Chat Syndrome Anju Zhang, Chengyun Zheng,

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Deletion of the Telomerase Reverse Transcriptase Gene and Haploinsufficiency of Telomere Maintenance in Cri du Chat Syndrome Anju Zhang, Chengyun Zheng, Mi Hou, Charlotta Lindvall, Ke-Jun Li, Fredrik Erlandsson, Magnus Björkholm, Astrid Gruber, Elisabeth Blennow, Dawei Xu The American Journal of Human Genetics Volume 72, Issue 4, Pages 940-948 (April 2003) DOI: 10.1086/374565 Copyright © 2003 The American Society of Human Genetics Terms and Conditions

Figure 1 Deletion of the hTERT gene and accelerated telomere shortening in patients with CdCS. A, Deletion of one hTERT allele in CdCS. A representative lymphocyte metaphase from a patient with CdCS is shown. The hTERT and 5q31 marker signals are labeled in red and green, respectively. The arrowhead indicates the chromosome 5 lacking the hTERT signal. Length (in μM) is represented by the scale bar. B and C, Visualization of telomeres on lymphocyte chromosomes from a patient with CdCS and an age-matched unaffected control individual, respectively, by using Q-FISH. Length (in μM) is represented by scale bars. D, Telomere length expressed as the total fluorescence intensity, assessed by using the Imp image-processing software, in metaphase lymphocytes from eight patients with CdCS (red square) and age-matched unaffected control individuals (blue circle) (CdCS: 11,668±1,887; control individuals: 34,208±2,923 [P<.0001, by Student's t test]). Bars indicate SEM (in some cases, the bar is invisible owing to SEM values that are too small). Arrowheads indicate two patients whose T cells expressed comparable levels of hTERT/telomerase activity when compared with matched control cells. E, Telomere length as determined using Southern blot. Typical smear signals of human telomeres are shown. The positions (in kb) of DNA molecular markers are indicated at left. “N” and “P” denote the age-matched control individuals and patients, respectively. The American Journal of Human Genetics 2003 72, 940-948DOI: (10.1086/374565) Copyright © 2003 The American Society of Human Genetics Terms and Conditions

Figure 2 Extension of life span, stabilization of telomeres, and prevention of chromosome fusions by expression of telomerase activity in fibroblasts from patients with CdCS. Telomerase-reconstituted fibroblasts at PD30 (right) from a 35-year-old patient, together with their parental cells at PD18 (left), were analyzed for β-Gal staining (Senescence biomarker) (A), telomere length (B), and chromosome fusions (C). C, Representative SKY results from one metaphase. Top, Fusion between chromosomes 5 and 22 (middle). The other chromosome 5 with a partial 5p deletion and the normal chromosome 22 are shown at right and left, respectively. Bottom, Fusion event between chromosomes 13 and 18 (middle). Normal chromosomes 13 and 18 from the same cell are shown at right and left, respectively. The American Journal of Human Genetics 2003 72, 940-948DOI: (10.1086/374565) Copyright © 2003 The American Society of Human Genetics Terms and Conditions

Figure 3 hTERT mRNA expression and telomerase activity in activated T lymphocytes derived from patients with CdCS. Unblackened and blackened columns show patients with CdCS and unaffected control individuals, respectively. A, hTERT mRNA levels in activated T cells from patients with CdCS. Top, hTERT mRNA signals as revealed by a competitive RT-PCR. β2-M RT-PCR was performed as internal controls. P1–P7 = patients in order of age; N1–N7 = matched unaffected control individuals; C = hTERT competitor. Bottom, Relative levels of hTERT mRNA which were calculated from signal ratio of hTERT mRNA and its competitor normalized to β2-M expression (as shown at top) (patients with CdCS: 1.9±0.8; control individuals: 3.4±0.7 [P<.05, by Student's t test]). B, Telomerase activity in activated T cells from patients and unaffected control individuals as measured by using a telomerase PCR-ELISA kit (patients with CdCS: 0.5±0.3; control individuals: 0.7±0.2 [P>.05, by Student's t test]). Relative levels of telomerase activity were arbitrarily expressed as absorbance (OD) at 450 nm. The American Journal of Human Genetics 2003 72, 940-948DOI: (10.1086/374565) Copyright © 2003 The American Society of Human Genetics Terms and Conditions