Studies on the first described Alzheimer's disease amyloid beta mutant, the Dutch variant.

[hereditary cerebral hemorrhage with amyloidosis]

Amyloid protein deposited in cerebral vessel walls and diffuse plaques of patients with hereditary cerebral hemorrhage with amyloidosis , Dutch type (HCHWA-D ), is similar to the 40 -42 residues amyloid beta (Abeta ) in vessel walls and senile plaques in brains of patients with Alzheimer 's disease (AD ), Down 's syndrome , and familial and sporadic cerebral amyloid angiopathy (CAA ). In 1990 we sequenced the amyloid beta -protein precursor (AbetaPP ) gene from HCHWA-D patients revealing a single mutation that results in an amino acid substitution , Abeta E 22 Q . Subsequent identification of additional mutations in the AbetaPP gene in familial AD (FAD ) pedigrees revealed that whereas substitutions in the middle of Abeta , residues Abeta 21 -23 , are predominantly vasculotropic , those found amino- or carboxyl-terminal to the Abeta sequence within AbetaPP enhance amyloid parenchymal plaque deposition . Studies of transfected cells showed that substitutions amino- or carboxyl-terminal to Abeta lead to either greater Abeta production or to enhanced secretion of the more hydrophobic thus more fibrillogenic Abeta 1 -42 . Substitutions in the center of Abeta facilitate rapid aggregation and fibrillization , slower clearance across the blood -brain barrier and perivascular drainage to the systemic circulation , possibly higher resistance to proteolysis , and enhanced toxicity towards endothelial and smooth muscle cells . However , most AD patients have no genetic defects in AbetaPP , indicating that other factors may alter Abeta production , conformation , and /or clearance initiating the disease process .

Diseases
Validation

Diseases presenting "single mutation" symptom

adrenomyeloneuropathy

cystinuria

hereditary cerebral hemorrhage with amyloidosis

oculocutaneous albinism

werner syndrome

x-linked adrenoleukodystrophy

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