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A Novel Mutation in ALK-1 Causes Hereditary Hemorrhagic Telangiectasia Type 2

¹ Department of Oral Medicine, Peking University School of Stomatology, 22 South Zhong Guan Cun Street, Beijing 100081, People’s Republic of China;
² Molecular Laboratory for Gene Therapy, School of Stomatology, Capital Medical University, 4 Tian Tan Xi Li, Chongwen District, Beijing 100050, People’s Republic of China; and
³ Chinese National Human Genome Center, 707 North Yongchang Road, BDA, Beijing 100176, People’s Republic of China

View larger version (13K): [in a new window]   Figure 1. The pedigree diagram of this Chinese Han family with hereditary hemorrhagic telangiectasia Type 2 (HHT2). The arrowhead indicates the proband of this family, indicates HHT2 patients, and indicates the normal family numbers. There are eight patients, including the proband, and 46 normal individuals in this family. It is an autosomal-dominant hereditary disease, according to genetic analysis.

View larger version (86K): [in a new window]   Figure 2. The lesions in patients with hereditary hemorrhagic telangiectasia type 2 in this Chinese Han family. All photographs were taken with the patients’ consent. (a) Lesions on the ventral surface of the tongue from patient No. III:7, who had severe bleeding on the tongue; (b,c,d) lesions on the dorsum of the tongue, on the thumb, and on the palms of patient No. III:10, who had bleeding of the tongue and fingers.

View larger version (20K): [in a new window]   Figure 3. ALK-1 gene mutation and protein expression. (a) Exon 10 sequencing results of gene ALK-1. (upper) The result of a normal control; (lower) the result of the patient in this family. The arrowhead indicates the mutation base. This is a C-to-T mutation in base 1717 of ALK-1 gene (1717C>T). This mutation resulted in an amino acid change, from Arg to stop codon (R479X) in the ALK-1 protein. (b) Western blotting verified that the ALK-1 protein was truncated. The protein was isolated from immortalized cells from both patients and normal family members. Lane 1 indicates the patient’s sample, and lane 2 is the sample from a normal individual. A smaller band in the ALK-1 protein from the patient’s sample indicates the truncated ALK-1 protein. The small band was not found in the sample from the normal individual. There were no significant differences in the protein expression levels of ALK-1 (-tubulin, the internal control).

View larger version (7K): [in a new window]   Figure 4. ALK-1 mRNA expression and plasma thrombomodulin (TM) level. (a) The expression of ALK-1 mRNA. From the results of the real-time quantitive PCR, the relative quantity is the ratio of ALK-1 mRNA/Alb (internal control). There were no significant differences of ALK-1 mRNA expression level among the patients (column 1, n = 6), the healthy individuals of the family (column 2, n = 7), and normal controls (column 3, n = 50). Results are expressed as means of 3 experiments in triplicate ± SD. (b) Plasma thrombomodulin of the patients (column A, n = 6) and healthy individuals (column B, n = 7) in this family, and of normal controls (column C, n = 50). There was a significantly higher thrombomodulin level in patients (p < 0.001) than in healthy individuals in this family and normal controls. No significant difference of plasma thrombmodulin level was found between healthy individuals in this family and normal controls. Results are expressed as means of 3 experiments ± SD.