Heparan sulfate, accumulation

This "Hurler corrective factor" was identified as an a-L-iduronidase. In the Hunter syndrome (MPS II) dermatan sulfate and heparan sulfate accumulate. 

Heparan ti-sulfalase. Heparan sulfate accumulates. No clouding of cornea. Heart not affected. Skeleton only slightly affected. Facial features similar to type but less severe. 

Glucosamine N-aceiyltransferase (EC 2.3.1.3). Heparan sulfate accumulates. Facial features similar to typelll. ... 

H-Acetyiglucosamme-6-sulfatase (EC 3.1.6.14). Heparan sulfate accumulates. Mild osteochondnxtystro-phy, and presence of hypoplastic odontoid proccss. Fadal features similar to type III a-ViPt mucopolysaccharidosis, or Morquio-Brailsfordsyndrome (variant 1) (see Fig.2). 

Hurler syndrome (MPS type I) is caused by deficiency of a-iduronidase, a lysosomal enzyme involved In degradation of dermatan sulfate and heparan sulfate, which accumulate in the cells of all tissues and spill over into the urine. 

First described in 1919 by Hurler, mucopolysaccharidosis I (MPS I, the Hurler syndrome) leads to accumulation of partially degraded dermatan and heparan sulfates (Fig. 4-11).317,352 353 A standard procedure in the study of diseases of this type is to culture fibroblasts from a skin biopsy. Such cells cultured from patients with the Hurler syndrome accumulate the polysaccharide, but when fibroblasts from a normal person are cultured in the same vessel the defect is "corrected." It was shown that a protein secreted by the normal fibroblasts is taken up by the defective fibroblasts, permitting them to complete the degradation of the stored polysaccharide. 

McCormick C, Duncan G, Goutsos KT, Tufaro F. The putative tumor suppressors EXTl and EXT2 form a stable complex that accumulates in the Golgi apparatus and catalyzes the synthesis of heparan sulfate. Proc. Natl. Acad. Sci. U.S.A. 93. 2000 97(2) 668-673. 

F-1) The mucopolysaccharidoses are proteoglycan disorders that generally result from a hereditary lysosomal defect in enzymes that normally degrade mucopolysaccharides (in most cases heparan sulfate and dermatan sulfate). This leads to the accumulation of different mucopolysaccharides, which may be associated with a variety of different findings, commonly including mental retardation and various skeletal abnormalities. These diseases include Hunter disease, Hurler and Scheie disease, I-cell disease , Maroteaux-Laury disease, Morquio syndrome, Mucolipidoses VH disease, multiple sulfatase deficiency, and Sanfilippo A and B diseases, which will not be elaborated on further here. Often these conditions can be detected in advance on amniocentesis. 

Excessive accumulation of proteins, nucleic acids, carbohydrates, and lipids can result from deficiency of one or more lysosomal hydrolases. Lysosomal storage diseases are classified by the stored material. Accumulation of gly-cosaminoglycans results in mucopolysaccharidoses. Common causes of this disorder include Hunter syndrome, Hurler syndrome, and Sanfihppo syndrome. Sanfdippo syndrome is inherited in an autosomal recessive pattern and clinically evident by profound mental retardation, lack of normal developmental milestones, and significant language delay. Sanfdippo syndrome results in an excess of heparan sulfate and can be caused by a variety of enzyme deficiencies. 

In Sanfilippo syndrome, the accumulation of heparan sulfate in lysosomes leads to severe neurologic and mental impairment that result in death usually by the end of the second decade of life. 

It is well known that the activities of various lysosomal hydrolases are strongly inhibited by heparan sulfate and other glycosaminoglycans (Avila and Convit, 1976). A possibility therefore exists that the primary defect in multiple sulfohydrolase deficiency is a mutation of hydrolase acting on heparan sulfate. An accumulation of this glycosaminoglycan may then inhibit other sulfohydrolases (Farooqui and Horrocks, 1984b). This possibility has not been tested. 

Ji ZS, Pitas RE, Mahley RW. Differential cellular accumulation/retention of apolipoprotein E mediated by cell surface heparan sulfate proteoglycans. Apo-lipoproteins E3 and E2 greater than e4. J Biol Chem 1998 273 13452-13460. 

In the Sanfilippo syndrome, glycosaminoglycan accumulates in ocular material (J14), and heparan sulfate is by far the predominant glycosaminoglycan accumulated in the liver (G9), and here the glycosaminoglycan is known to be polydisperse. Heparan sulfate also accumulates... 

Iduronale-2-sutfatase (EC 3.1.6.13). Heparan sulfate and dermatan sulfate accumulate. No clouding of cornea. Heart involvement rare. Mental retardation less than in typelu. Fadal features similar to type 1h- lype Ilg slightly less severe than IIa... 

Glucuronidase (EC 3.2.1.31). Chondroitin 4-sulfate and chondrotin 6-sulfate accumulate. Dermatan sulfate and/or heparan sulfate sometimes also accumulate. Mental retardation not severe. Cornea sometimes clouded. Facial appearance may resemble type Ih, or may be less severely affected, or normal. Skeletal deformities usually very marked. Heart not affected... 

Several inherited diseases of connective tissues are known (McKusick, 1966), some of which involve a derangement of glycosaminoglycan metabolism, and, in particular, Hurler s syndrome has been extensively studied in many laboratories (Dorfman, 1966a Dorfman and Matalon, 1969). The disorder expresses itself biochemically as an accumulation of glycosaminoglycans in various tissues (particularly dermatan sulfate and heparan sulfate), and recent work by Fratantoni si al. (1968) and Neufeld and Fratantoni (1970) suggests that there is a defect in degradation of the glycosaminoglycans rather than an overproduction. 

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