Structure of the human liver/bone/kidney alkaline phosphatase gene and the genetic basis for hypophosphatasia / Mitchell J. Weiss.

Format:

Book

Manuscript

Microformat

Thesis/Dissertation

Author/Creator:

Weiss, Mitchell J.

Contributor:

Harris, Harry, advisor.

University of Pennsylvania.

Language:

English

Subjects (All):

Penn dissertations--Genetics.

Genetics--Penn dissertations.

Dissertations, Academic.

Genetics.

Medical Subjects:

Genetics.

Local Subjects:

Penn dissertations--Genetics.

Genetics--Penn dissertations.

Dissertations, Academic.

Physical Description:

xi, 121 leaves : illustrations ; 29 cm

Production:

1989.

Summary:

Alkaline phosphatases are a group of enzymes that hydrolyze a variety of monophosphate esters at high pH optima. They are present in most forms of life. In man, there are three distinct forms of ALP encoded by separate genes: placental, intestinal and liver/bone/kidney (L/B/K). A fourth gene locus encodes a placental-like ALP expressed in germ cells. The biological function(s) of ALP are unknown except that the enzyme is involved in bone formation, as evidenced by hypophosphatasia, a rare heritable disorder characterized by defective skeletal mineralization and a deficiency of L/B/K ALP activity.

For years, study of the ALP gene family was limited to examination of its enzyme products. Recently, our lab and others have begun to characterize the corresponding genes. This thesis describes the cDNA and gene encoding L/B/K ALP. Comparison of these structures to the cDNAs and genes encoding the other major forms of ALP further delineates the evolutionary history of this multi-gene family.

To study hypophosphatasia, fibroblasts were examined from 14 severely affected patients. These cells were deficient in L/B/K ALP activity but produced normal levels of the corresponding mRNA. Materials from one family were examined in further detail. The proband was homozygous for a point mutation that substitutes alanine-162 of the mature enzyme with threonine. Introduction of this mutation into an otherwise normal cDNA disrupted enzymatic activity of the resultant polypeptide, demonstrating that a defect in the L/B/K ALP gene results in hypophosphatasia.

Notes:

Supervisor: Harry Harris.

Thesis (Ph.D. in Genetics) -- Graduate School of Arts and Sciences, University of Pennsylvania, 1989.

Includes bibliography.

Local Notes:

University Microfilms order no.: 89-22626.

OCLC:

244968265