本論文以台灣體染色體隱性遺傳的第一型黏多醣儲積症（MPS I）及染色體顯性遺傳的家族性表面蛋白B-100缺陷（FDB）患者為對象，進行患者分子致因及相關的研究。
第一型黏多醣儲積症部分是以聚合鏈反應（PCR）、單股核酸構形多型性（SSCP）及DNA定序法，檢視台灣二位第一型黏多醣儲積症患者的分子致因。結果發現患者D4對偶基因1發生1447del27突變（缺失胺基酸密碼454-462及絲胺酸453→精胺酸）；對偶基因2上發生1474ins15突變（第463個胺基酸位置插入5個胺基酸）。患者L5亦為異型合子的突變，其遺傳自母親的對偶基因發生L346R（第346個胺基酸密碼發生T→G顛換）；遺傳自父親的對偶基因則發生388-3c>g（介入子2的3'裁接接受點-3位置由C轉變成G）。含突變1447del27、1474ins15的IDUA重組質體轉移入COS-7細胞時所表現的酵素活性分別為野生型之0.1 %、0.3 %，所表現的mRNA量分別為野生型的24 %、49 %，所表現的IDUA蛋白質，則在IDUA多株抗體偵測底線之下。故D4患者的缺失及插入突變導致幾乎無法表現有活性的IDUA酵素，因此造成患者臨床上嚴重的Hurler型性狀。含L346R點突變的重組質體轉移細胞所表現的IDUA蛋白質及mRNA與野生型相較，無顯著差異，然而其所表現的IDUA酵素活性僅為野生型之0.4 %。含388-3c>g突變的對偶基因表現的mRNA量非常低，且約有4 % mRNA進行裁接時採用介入子2 3'裁接點區域中-58的cryptic CAG當裁接點，造成58個核酸的插入突變。包含突變的3'裁接點區域的重組質體，在COS-7細胞中表現時，大部分mRNA無法進行裁接，顯示3'裁接接受點-3位置為胞嘧啶（cytosine）的重要性。
家族性表面蛋白B-100缺陷部分是以異偶合（Heteroduplex）分析、單股核酸形多型性（SSCP）分析及DNA定序等技術，檢視此樣品群apoB基因胺基酸位置3500附近的345 bp的DNA片段。結果發現二種點突變，其中ACA3528→ACG的變異並未改變所對應的胺基酸。而CGG3500→CAG的變異，造成精胺酸3500→麩胺酸醯胺（即FDB R3500Q突變）。在本研究的373個台灣的第二型高脂血症的樣品群中，一位具R3500Q突變（0.3 %；95 % CI：0.01- 1.5 %），9位具R3500W突變（2.4 %；95 % CI：1.1- 4.5 %），顯示R3500Q突變並不是造成中國人中度高脂血症的顯著因子，R3500Q患者家族的分析發現另二位R3500Q攜帶者且皆為高脂血症患者。進一步以多型性標記對突變基因進行單套型分析，結果發現R3500Q突變的單套型與報導的旅居美國舊金山華人的R3500Q相同，而不同於旅居加拿大華人的單套型。由此可知華人的R3500Q突變至少有二種不同的起源。

The purpose of this study is to investigate two human genetic disorders, mainly autosomal recessive - mucopolysaccharidosis type I (MPS I) and autosomal dominant - familial defective apolipoprotein (apo) B-100 (FDB), at molecular level in Taiwan.
In the study of MPS I, DNA screening for α-L-iduronidase (IDUA) gene mutations for two Chinese MPS I patients was performed by polymerase chain reaction (PCR), single-strand conformation polymorphism (SSCP), and DNA sequencing analysis. The D4 patient has 1447del27 (Ser453→Arg in addition to in frame deletion of codons 454-462) in one allele and 1474ins15 (in frame insertion of 5 unrelated amino acids at codon 463) in the other allele. Patient L5 also has heterozygous mutations; the maternal allele has L346R (T to G transversion in codon 346) and the paternal allele has 388-3c>g (C to G transversion at position -3 of the 3' splice site of intron 2). Expression of recombinant IDUA cDNA containing 1447del27 or 1474ins15 mutation showed traced amounts of α-L-iduronidase activity (0.1 %, 0.3 %) compared to that of normal cDNA upon transfection into COS-7 cells. By northern blot analysis, 24 % 1447del27 mRNA and 49 % 1474ins15 mRNA were detected. The IDUA protein produced by 1447del27 and 1474ins15 mutations was beyond the detection by IDUA polyclonal antibody. The data suggest that the 1447del27 and 1474ins15 mutations result in the severe Hurler phenotype of the D4 patient. In transfected COS-7 cells, L346R showed no appreciable α-L-iduronidase activity (0.4 % of normal activity), although it did not cause apparent reduction in IDUA mRNA or protein level. The 388-3c>g mutation caused a significant decrease in the level of IDUA mRNA. In about 4 % time, the mutation caused the cells to use a cryptic CAG sequence 58 bp upstream from the 3' splice site and lead to insertion of 58 intronic nucleotides. IDUA cDNA containing mutated acceptor splice site showed low efficiency of splicing in expression study. The results provide further support for the importance of cytosine at -3 position in RNA processing.
In the study of FDB, the apo B gene segment around codon 3500 was screened by heteroduplex analysis, single strand conformation polymorphism (SSCP) analysis and DNA sequencing analysis in a total of 373 hyperlipidemic individuals. Two single-base mutations were detected. One mutation, ACA3528→ACG change, resulted in degenerate codon with no amino acid substitution. The other mutation, CGG3500→CAG mutation, resulted in an Arg3500→Gln substitution (R3500Q). The prevalence of heterozygote in this selected population was 0.3 % (95 % confidence interval, 0.01-1.5 %) for the R3500Q mutation, and 2.4 % (95 % confidence interval, 1.1-4.5 %) for the previously described R3500W mutation. The results suggest that R3500Q mutation is not a significant factor contributing to moderate hypercholesterolemia in Chinese (P = 0.027). Family studies of the R3500Q carrier revealed an extra two individuals heterozygous for the mutation, and both of them were hypercholesterolemic. An analysis of the R3500Q allele using 6 diallelic markers and the 3'HVR marker revealed a haplotype which was the same as that reported in a Chinese American but differed from that reported in a Chinese Canadian. The data support limited multiple recurrent origins for R3500Q in Chinese population.

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