课件：疾病的单基因遗传.ppt

03 疾病的单基因遗传 Monogenic Inheritance,single-gene disorder or monogenic disorder Some disorders result when a mutation causes the product of a single gene to be altered or missing. These disorders are inherited in simple patterns similar to or identical with those described by Mendel for certain discrete characteristics in garden peas. Therefore, its also called Mendelian diseases.,3, 病例分析,姓名：不幸 男性，69岁，已3次经中南大学湘雅二医院临床确诊异时性结直肠癌，即52岁时诊断为右半结肠癌，61岁发生乙状结肠癌，68岁患直肠癌。,家族史：先证者的儿子于25岁和37岁两次诊断为异时性结直肠癌。其家族4代31人中有17人共21例次诊断结直肠癌等恶性肿瘤，其中12名(70.6 %)患者患有结直肠癌, 另6名患者发现结直肠外恶性肿瘤,包括子宫内膜、胃、脑、肝脏等。 所有患者恶性肿瘤的平均发病年龄是41岁, 结直肠癌的平均发病年龄是42.9岁, 患者的男女性别比例是107。,1. Pedigree and Proband,Humans are unique among organisms in many ways, but one way which is near and dear to a geneticists heart is that humans are not susceptible to genetic experimentation.,The study of inherited Mendelian traits in humans must rely on observations made while working with individual families.,Classical cross fertilization breeding experiments as performed by Mendel are not allowed in humans! Human geneticists are not allowed to selectively breed for the traits they wish to study!,One of most powerful tools in human genetic studies is pedigree analysis.,pedigree They are graphic representations of a family tree which show the biological relationship of the index case, or proband or propositus to the rest of the individuals. A family tree diagram that shows how a particular genetic trait or disease has been inherited.,When human geneticists first began to publish family studies, they used a variety of symbols and conventions. Now there are agreed upon standards for the construction of pedigrees.,Symbols,12,调查资料绘制系谱,家族史：先证者的儿子于25岁和37岁两次诊断为异时性结直肠癌。其家族4代31人中有17人共21例次诊断结直肠癌等恶性肿瘤，其中12名(70.6 %)患者患有结直肠癌, 另6名患者发现结直肠外恶性肿瘤,包括子宫内膜、胃、脑、肝脏等。 所有患者恶性肿瘤的平均发病年龄是41岁, 结直肠癌的平均发病年龄是42.9岁, 患者的男女性别比例是107。,?,14,判断遗传性非息肉性结直肠癌的阿姆斯特丹I标准： 家族中至少有3例组织病理学证实的结直肠癌患者，其中1例是另外2例的一级亲属； 至少有连续两代人发生结直肠癌； 至少有1例患者是在50岁之前发病； 排除家族性腺瘤性息肉病。,结直肠癌是一种最常见的内脏恶性肿瘤,发病率较高，其中大约有1520为家族性发病, 如家族性腺瘤息肉（Familial adenomatous polyposis, FAP）和遗传性非息肉性结直肠癌（Hereditary nonpolyposis colorectal cancer, HNPCC）。,寻找致病基因 及致病突变,遗传性非息肉性结直肠癌(HNPCC)的发生与DNA错配修复缺陷有关，已知至少有5种错配修复（mismatch repair，MMR）基因(MSH2、MLH1、MSH6、PMS1 和PMS2 )与其有关。目前已在HNPCC患者中发现了400多种MMR 基因的突变，其中 MSH2 基因突变约占50，MLH1 基因突变约占39。,15,MSH2 和MLH1 基因筛查,通过PCR扩增和序列测定, 在先证者 gDNA 中发现了MSH2 基因7号外显子中的一种国内外尚未见报道的新突变,该突变由于4个核苷酸（CCGA）的插入导致该4个核苷酸重复 (MSH2: c.1215_1218dupCCGA)，形成移码突变，产生异常截短蛋白。所有被检测的患者均发现该突变，表型正常的成年家系成员均正常。另外，50个家系外正常对照中未发现该基因突变。我们确认该突变导致了该家系的遗传性非息肉性结直肠癌的发生。,16,17,症状前诊断,家系中1人（IV-1）为突变基因携带者。该携带者（IV-1）年仅16岁，由于年龄尚小，尚未到发病年龄，目前未检出结直肠癌或其他癌症，但应引起高度重视。,MSH2 mutation,遗传性非息肉性结直肠癌,Autosomal dominant inheritance,2. Autosomal dominant inheritance,The pattern of autosomal dominant inheritance is perhaps the easiest type of Mendelian inheritance to recognize in a pedigree. One dose of the mutant gene, one mutant allele, is all that is required for the expression of the phenotype.,There are three reasons why an individual with an autosomal dominant disease should always be considered as being a heterozygote until proven otherwise.,homozygotes？,heterozygotes？,Suppose a father is heterozygous for an autosomal dominant gene, with allele D, the mutant dominant allele, and allele d, the recessive normal allele. He can produce two types of gametes, D and d. Suppose also his wife is homozygous normal, having both d alleles. The Punnett Square is constructed as follows:,One gamete comes from each parent to produce the genotype of the offspring. Two out of the four possible combinations are affected; two out of four are normal.,Sample Pedigree,?,With the understanding that almost all affected individuals are heterozygotes, and that in most matings involving a person with an autosomal dominant trait the other partner will be homozygous normal, there are four hallmarks of autosomal dominant inheritance.,There are four hallmarks of autosomal dominant inheritance: (1) Except for new mutations, which are rare in nature and extremely rare on examination pedigrees, and the complexities of incomplete penetrance to be discussed later, every affected individual has an affected biological parent. There is no skipping of generations. (2) Males and females have an equally likely chance of inheriting the mutant allele and being affected. The recurrence risk of each child of an affected parent is 1/2.,(3) Normal siblings of affected individuals do not transmit the trait to their offspring. (4)The defective product of the gene is usually a structural protein, not an enzyme. Structural proteins are usually defective when one of the allelic products is nonfunctional; enzymes usually require both allelic products to be nonfunctional to produce a mutant phenotype.,?,3. Autosomal recessive inheritance,the recessive affected individual the heterozygous carrier individual the homozygous normal individual,dd,Dd,DD,affected individuals have parents with normal phenotypes.,The first, and most important,Suppose the disease affects one in ten thousand live births the heterozygote frequency in the population one in fifty (see population genetics for calculations).,The Punnett Square for autosomal recessive diseases with an affected child in the family almost always looks like the following:,Where the father and mother are both Dd. The Punnet Square shows the origin of the famous Mendelian ration of 3/4 normal to 1/4 affected.,For most autosomal recessive diseases, but not all, the heterozygote cannot be distinguished from the normal homozygote. In the normal phenotype categories of offspring in the above Punnett Square (Dd and DD produce the same normal phenotype), please note that two of the three are heterozygotes (carriers); one of the three is homozygous normal.,Within the normal siblings of an affected individual the probability of being a carrier is 2/3.,There are five hallmarks of autosomal recessive inheritance: (1) Males and females are equally likely to be affected. (2) On average, the recurrence risk to the unborn sibling of an affected individual is 1/4. (3) The trait is characteristically found in siblings, not parents of affected or the offspring of affected. (4) Parents of affected children may be related. The rarer the trait in the general population, the more likely a consanguineous mating is involved. (5) The trait may appear as an isolated (sporadic) event in small sibships.,Sample pedigree,?,When consanguinity is involved, i.e., matings between related individuals, in the production of an affected child the assignment of probabilities changes, especially in the rarer autosomal recessive diseases.,Sample pedigree, 为什么近亲婚配时子女发病风险明显增高？,在34代之内有共同祖先的个体之间的婚配称为近亲婚配。,有共同祖先的两个个体，在某一基因座上带有相同基因（由共同祖先传递来）的概率用亲缘系数(coefficient of relationship)衡量。,2019/8/20,43,可编辑, 依据亲缘系数的大小，分成不同的亲属级别,家族无患者时，近亲婚配发病风险增高,某种AR，致病基因频率为1/1001/1000 携带者频率为1/501/500（2pq） 随机婚配 1/50 X 1/50 X 1/4=1/10000 近亲婚配 1/50 X 1/8 X 1/4= 1/1600 1/500 X 1/500 X 1/4=1/1 000 000 1/500 X 1/8 X 1/4= 1/16000,群体中AR遗传病的携带者频率越低，近亲婚配后代的相对发病风险就越高。,家族有患者时，近亲婚配时子女发病风险明显增高,设某种AR遗传病的发病率为1/10000,近亲婚配时： 1/31/31/4,随机婚配时： 1/31/501/4,1的发病风险为：2/3 1/41/4,例如：婴儿黑朦性痴呆,患者眼底病变,例如：肝豆状核变性,苯丙酮尿症（PKU）, 遗传方式：AR 关 键 酶：苯丙氨酸羟化酶（PAH） 基因定位：12q22-24 PAH基因全长85kb，含13个外显子 基因缺陷以点突变为主 临床表现： 苯丙酮酸苯乳酸苯乙酸 毛发、皮肤和尿有特殊气味 患者毛发和皮肤颜色浅,苯丙氨酸 酪氨酸 多巴 儿茶酚胺,苯丙酮酸,苯乙酸 苯乳酸,尿黑酸,乙酰乙酸,黑色素,甲状腺素,苯丙氨酸、酪氨酸代谢,白 化 病, 遗传方式：AR 关 键 酶：酪氨酸酶 基因定位：11q14-21 基因全长50kb，含5个外显子 基因缺陷以点突变为主 临床表现： 皮肤、毛发淡黄色或银白 虹膜及瞳孔呈淡红色，羞明，眼球震颤 易患皮肤癌,白 化 病,白化病典型家系,4. X-linked dominant inheritance,When an X-linked gene is said to express dominant inheritance, it means that a single dose of the mutant allele will affect the phenotype of the female. A recessive X-linked gene requires two doses of the mutant allele to affect the female phenotype.,Affected father x normal mother. Affected mother x normal father.,hemizygote,Criss-cross inheritance,The following are the hallmarks of X-linked dominant inheritance: (1)The trait is never passed from father to son. (2)All daughters of an affected male and a normal female are affected. All sons of an affected male and a normal female are normal. (3)Matings of affected females and normal males produce 1/2 the sons affected and 1/2 the daughters affected. (4)Males are usually more severely affected than females. The trait may be lethal in males. (5)In the general population, females are more likely to be affected than males, even if the disease is not lethal in males.,Sample pedigree,?,Incontinentia pigmenti,Vitamin D-resistant Rickets,5. X-linked recessive inheritance,Everyone has heard of some X-linked recessive disease even though they are, in general, rare. Hemophilia, Duchenne muscular dystrophy, Becker muscular dystrophy, and Lesch-Nyhan syndrome are relatively rare in most populations, but because of advances in molecular genetics they receive attention in the media.,The hallmarks of X-linked recessive inheritance (1) As with any X-linked trait, the disease is never passed from father to son. (2) Males are much more likely to be affected than females. (3) All affected males in a family are related through their mothers. (4) Trait or disease is typically passed from an affected grandfather, through his carrier daughters, to half of his grandsons.,Sample pedigree,?,Hemophilia,DMD,6. Y-linked,A gene on the Y chromosome. A Y-linked gene is by necessity passed from father to son, since the Y chromosome can only be transmitted by a man to his male progeny.,A number of genes were known to be Y-linked including: ASMTY (acetylserotonin methyltransferase), TSPY (testis-specific protein), IL3RAY (interleukin-3 receptor), SRY (sex-determining region), TDF (testis determining factor), ZFY (zinc finge