Chapter 10 Non-mendelian Inheritance

10.1 다인자성 유전질환

- 다인자성(혹은 부분유전성) 형질은 연속적(키) 혹은 불연속적(당뇨병)

- 여러개의 유전인자가 부가적으로 작용

- 환경적 요인의 영향

- 환자가족의 발병률은 비환자가족(집단의 발병률)에 비해 높다.

- 가족내에서는 Mendelian 형질 유전보다 발병률이 낮다

- 가계도만으로는 다인자성 유전인지 유전과 무관한 질병인지 알기 힘듬

- 따라서, 쌍둥이 일치도와 가족연관성을 조사해야함

10.2 쌍둥이 일치도

- 쌍둥이는 일란성, 이란성

- 일란성은 유전적 동일, 이란성은 유전적으로 형제와 동일

- 일란성과 이란성의 구분 : 태반막의 기록 사용

- 이란성은 항상 두개의 양막과 요막을 갖게됨

- 일란성은 분리시기에 따라 태반막이 다름, 75%는 단일 요막, 나머지 25%는 두개의 요막과 양막을 가고 있어서 이란성과 구분이 안됨--> DNA fingerprinting 필요

10.2.1 일치도 결정

- 두 쌍둥이가 같은 불연속적 형질을 보이면 일치한다고 함

- 연속적 형질(예, 키)의 경우 두 사람을 직접비교하지만 일반적으로 두 사람이 같은 환경에서 자라므로 그 형질에 대한 유전적인 기여와 환경적인 기여를 구분하기가 힘들므로 유아기부터 다른 환경에서 자란 쌍둥이를 조사하는 것이 필요.

10.2.2 쌍둥이 연구의 결과

- 일란성은 동일한 유전형, 이란성은 유전적으로 형제와 같다

- 단일 유전자성 형질 : 일란성은 100% 일치도, 이란성은 형제간의 일치도와 동일

- 다인자성 불연속적 형질(유전적, 환경적 요인의 영향을 받는 경우) : 일란성은 100% 이하, 이란성보다 높음

- 연속적 형질, 선천성 기형, 일반 성인 질환에서의 일치도(Table  10.2, 10.3): 일란성이 이란성 보다 일치도 높음. 일치도는 유전성을 반영

10.3 가족 상관성 연구

- 친족관계는 유전적으로 일부를 공유(Table 10.4)

- 다인자성 유전의 경우 유전적 동일성의 정도에 의해 형질이 결정됨

- 친족간의 형질의 유사성을 상관성이라고 함(동일시 상관성은 1)

- 연속적 형질의 상관성(Table 10.5)

- 친족간 불연속적 형질의 발생 빈도(Table 10.6)

- 쌍둥이 일치도와 가족 상관성 연구는 연속적 혹은 불연속적 형질의 다인자성 유전을 밝히는데 사용됨

- empiric risk: 비멘델성 유전의 경우 경험적 발생 위험도: 유전상담에 이용

(Empiric risk: The chance that a disease will occur in a family based upon experience (past history, medical records, etc.) rather than theory)

10.4 연속적 다인자성 형질

- 연속적 다인자성 형질의 특징 : 연속적 분포(정상분포:Gaussian), 즉 대부분이 평균치 부근에 위치.

- 정상분포를 하는 이유는 다인자성이기 때문, 즉 여러 가지의 유전자가 상호작용하여 형질이 발생(Fig. 10.3)

10.5 불연속적 다인자성 형질

- 20가지 이상이 알려짐(선천성 기형 등)

- 예, 언청이: 부모가 정상일 경우 부모는 언청이 관련 유전자를 일부 갖고 있으나, 정상 유전자를 충분히 갖고 있다고 볼 수 있다. 자식은 언청이를 일으키는 유전자들의 비율이 높아서 발병(역치이상으로 언청이 유전자의 비가 증가)

- 발병성향 곡선(Fig. 10.5) : 정상분포. 집단에서 역치 이상이 차지하는 비율이 일반집단의 발병률.

- 유전병환자의 first-degree relative의 발병성향곡선은 우측으로 이동

- 증상이 심하면 심할수록 발병성향곡선은 우측으로 이동

- 어떤 다인자성 유전형질은 성에 따른 발생빈도가 다름

예) 유문협착증: male은 5/1000, female은 1/1000 따라서, 여성환자의 친족은 발생빈도가 더 높다(Carter 효과 Table.10.10). 즉 여성의 역치가 더 높음

10.6 체세포성 유전질환

- 제1분열 후 발생: mosaic

- 돌연변이가 생식선에 국한되어 발생: 생식선 mosaic

- 돌연변이가 체세포에 국한되어 발생: 체세포성 mosaic

1.7 Mitochondrial disorder

- 미토콘드리아 돌연변이는 체세포 보다 10 배 높음

- 각 미토콘드리아내에 정상 미토콘드리아 게놈과 돌연변이된 것이 공존하는 경우가 흔함(heteroplamy)---> 그 비율에 따라서 증상이 다름. heteroplasmy의 경우 세포분열시 모두정상 혹은 모두 이상인 미토콘드리아가 생성(homoplasmy)--> heteroplasmy가 있는 사람의 경우 시간이 지날수록 발병

Heteroplasmy is the presence of a mixture of more than one type of an organellar genome (mitochondrial DNA (mtDNA) or plastid DNA) within a cell or individual. Since every eukaryotic cell contains many hundreds of mitochondria with hundreds of copies of mtDNA, it is possible and indeed very frequent for mutations to affect only some of the copies, while the remaining ones are unaffected

Homoplasmy is the presence of a mutation affecting all of the mitochondrial DNA (mtDNA) copies in a cell. Since there are hundreds or even thousands of mtDNA copies in every eukaryotic cell, mutations may either be present in all copies (homoplasmy) or affect only a fraction of them (heteroplasmy).

Homoplasmy = a state in which all the mitochondria of a cell or a tissue have the same genome, which may be either the wild type genome or a mutated one.

Leber’s hereditary optic neuropathy (LHON) or Leber optic atrophy is a mitochondrially inherited (mother to all offspring) degeneration of retinal ganglion cells (RGCs) and their axons that leads to an acute or subacute loss of central vision; this affects predominantly young adult males. However, LHON is only transmitted through the mother as it is primarily due to mutations in the mitochondrial (not nuclear) genome and only the egg contributes mitochondria to the embryo. LHON is usually due to one of three pathogenic mitochondrial DNA (mtDNA) point mutations. These mutations affect nucleotide positions 11778, 3460 and 14484, respectively in the ND4, ND1 and ND6 subunit genes of complex I of the oxidative phosphorylation chain in mitochondria. Men cannot pass on the disease to their offspring

International Foundation for Optic Nerve Disease

P. O. Box 777, Cornwall NY 12518, USA

Leber Hereditary Optic Neuropathy (LHON), also known as Leber Optic Atrophy (LOA), was first described in 1871 as a sudden loss of vision in young men with a family history of blindness. It is the most common of the hereditary Optic Atrophies.

[Note: LHON or LOA should not be confused with either Leber's Congenital Amaurosis or Leber's Miliary Aneurysms which are unrelated eye conditions.]

Symptoms and Signs of LHON

The disease causes a loss of central vision within two to eight weeks, usually affects both eyes, may cause eye pain or discomfort at first, and may cause neurological symptoms such as numbness and tingling. Ophthalmologists detect signs of optic nerve degeneration such as visual field defects, blood vessel changes around the optic disc, optic disc pallor, pupil reflex abnormalities, and color vision abnormalities.

Causes

The reason for the sudden visual loss in LHON was unknown until recently. In 1988 researchers discovered that LHON is one of a group of mitochondrial diseases --genetic diseases that are inherited only through the mother. Mitochondria are the bodies within cells where energy needed for the activities of the cell is produced from oxygen. There are now some twenty different genes known to take part in the development of LHON. Three particular mutations account for 85% to 90% of the cases of LHON.

The factors that render mitochondria in optic nerve cells unable to produce energy thereby producing cell death, are largely unknown. One hypothesis (Wallace et al 1997), is that cell death is actually programmed, and is the result of a random distribution of defective mitochondrial DNA during the normal division and ageing process of cells (mitosis).

Diagnosis

The discovery that LHON is a mitochondrial disease has led to a diagnostic blood test now available in a few centers mainly in the United States, Europe, Japan and Australia. The test is 100% accurate for LHON when visual loss has already occurred. Family members of someone with LHON who test positive may be at risk for LHON. It is important for family members to be tested because changes in lifestyle and diet may help prevent the onset of LHON. If you or someone you know has had a sudden visual loss that cannot be corrected by glasses and the diagnosis is unknown, IFOND may be able to help with names of specialists in optic nerve disease near where you live.

Incidence

Current research reveals that while LHON occurs 80% of the time in young men in their twenties, it also occurs in men, and in women, of all ages. In one recent study the onset of LHON was found to have occurred in men and women as young as six and as old as sixty two. Other research finds that LHON may occur in someone who has no family history of LHON or blindness. The incidence of LHON is thought to be ............ Since the test is so new and many eye care specialists do not yet know about it, the real incidence is still unknown.

Risk Factors for Onset Of Blindness

Genetic Markers Present - A simple painless test using hair, cheek, and blood cells can be performed to genetically type your mitochondria. If there is a family history of sudden onset of blindness, whatever age, it is wise to check this out as the understanding of this disease process is relatively new and the ability to test and classify the genes has only been available for the last ten (10 ) years. The tests are only performed in certain centres around the world, and your samples may have to be sent some distance. Blood may be safely sent using a Western Blot technique.

Genotype - There are many different areas within the mitochondria that may be affected. The area, or site on the mitochondria DNA that contains the mutation is expressed as a number. Up to 80% of the mutations documented are 11778, 3460, and 14484. However research is showing that there are other mutations. The prognosis for loss of vision is poor for the 11778.

Mature Males Predominate - If you are male with the LHON mitochondria and are between the ages of 26 to 45 you may be more at risk of developing the disease.

Homoplasmy - Of those that have affected mitochondria, some have a greater ratio of "affected" to "normal" mitochondria. This is usually expressed as a percentage. For instance, if some normal mitochondria were detected amongst the cells tested you may have a 92% affected level also known as heteroplastic mitochondria. If all measured mitochondria are affected you may be more at risk. 100% affected would be called homoplastic. Many people with documented homoplasty still have normal vision, however.

Toxic substances - ingested, inhaled or absorbed through the skin, have been shown to cause neurological and optic blindness and it is suggested that those people with genetic deficiencies of the mitochondria may be more susceptible to small amounts of these sorts of substances. More work is needed to determine whether mitochodrial deficiency results in increased susceptibility. The toxic substances shown to cause blindness include:

Tobacco smoke

Alcohol

Some antibiotics

Cancer treating drugs

Anti-viral drugs eg. as used for treating AIDS.

Anti malarial drugs

Some anti arrythmic heart drugs

Some anti high blood pressure drugs

Some anti epilepsy drugs

(Possibly)Cyanogens These are found in some foods such as peas, beans, and other legumes, almonds and other nuts, and apricots. Cigarette smoke also contains quantities of these substances.

Fumes from Paints, Varnishes, hair dyes, especially fat soluble chemicals including Benzene rings in their chemical structure eg Toluene. The cell membrane of the nerve cell has a lipid (fat) layer and these neurotoxins may be aided to penetrate with the benzene components.

Stress related chemicals eg Adrenaline, catecholamines, possibly testosterones ( 2 documented cases of blindness) and other oxidating chemicals endogenously released by the body.

and others

For those at risk a double check with your doctor and pharmacist is highly recommended before taking a course of drugs for any reason.

Possible Protective Factors

Unfortunately, at present there is no cure for LHON. For now prevention, with avoidance of possible toxins, and judicious use of antioxidants when toxins are unavoidable, is the cornerstone of hope. In case of an acute onset of blindness in a recognised family pedigree of Leber's, it is important if at all possible, to be monitored by an ophthalmologist.

Protective genes. As there are many more cases of male onset of blindness than female, it is postulated that there is some protective factor in the female body. So far a related X chromosome marker has not been found. It is possible that female hormones such as progesterone offer some protective factor. A search for protective genes on other chromosomal and mitochondrial DNA continues.

Treatment (?)

Though no treatment has proven benefit for LHON, therapy may be indicated for other incidental disease which could possibly delay or prevent onset of blindness.

Reports of cure with drugs in isolated LHON cases may be spontaneous recoveries which are known to happen in some mutations more than others. Or the intervention may have meant the difference for that individual. The reasons for these "cures" remain a mystery.

Research

Speculative lines of research in LHON therapy include the following:

Antioxidants may be the key to providing stability to the nerve cell and decreasing the likelihood of oxidative damage caused by free radicals released when cells are destroyed by chemical toxins. Antioxidants can be classified according to drug type and include Vitamins and natural plant extracts, for example, Vitamin E, Co-enzyme Q, Vitamin C, Vitamin A, Ginkgo biloba. There is some ancedotal evidence for ubiquinone [coenzyme Q10] mildly altering progress or recovery in some mutations.

Laboratory research continues on virus vector gene therapy and stem cell therapy. These lines of treatment have been used experimentally in people with other nerve injuries and diseases, but not in LHON.

Therapy with near infrared light emitting diodes [LED] has been trialled briefly in patients already affected with LHON to monitor the safety of the procedure. Near infrared LED has been shown to spare optic nerve damage in methanol poisoned rats. Methanol posioning is thought to have a mitochondrial mechanism. No LED treatment studies in evolving LHON have been completed. SAFETY NOTE: LED light therapy is done with eyes closed. Never shine LEDs or laser light into open eyes. This can cause permanent retinal damage.

The sparse negative anectodal evidence of Hyperbaric Oxygen Therapy [HBO] treatment specifically in LHON is not encouraging. This is not currently a line of active research in LHON. HBO has been suggested as a treatment by delivering increased levels of oxygen to the affected nerve cell during its "starvation" period, or period of onset of blindness. A counter argument is that too much oxygen may be toxic in the context of poor cell antioxidant functioning. Oxygen toxicity to the eye is a potential problem.. There has been some success, however, using HBO with with other nerve diseases.

Scientists believe research in Leber's Hereditary Optic Neuropathy (LHON) may provide the key to a better understanding of the disease process in other optic nerve diseases and in other widespread neurodegenerative diseases.

For example, the crucial cellular damage which leads to nerve cell death and blindness in Leber's Hereditary Optic Neuropathy is similar to nerve cell damage that occurs in Parkinson's and Alzheimer's Disease. These two common, slowly progressing neurodegenerative diseases affect millions in the United States alone. The time span of the disease process in LHON is more rapid, two to eight weeks. Finding the reason for this intriguing difference in timing may give clues to the eventual cures of these and other eye and nervous system diseases.

Research in LHON is ongoing and of prime importance, as this is a "model" disease, where genetic markers allow scientific data to be gathered. This data may be of importance not only for LHON affected families but for millions of others affected by Alzheimer's, Parkinson's Disease, glaucoma and many other diseases.

Why do some children who have inherited mitochondrial mutations responsible for LHON become blind while their siblings, born with the same mutations do not develop LHON? It is clear that genetic inherited mutations are not sufficient alone to explain blindness. What other factors may play a role?

Do the risk factors now known to cause blindness in some cases, actually stimulate the development of LHON? If so, how? Are there other risk factors? It seems clear from current knowledge that environmental risk factors play an important role in the onset of LHON but much more needs to be learned about the known potential risk factors, and the possible existence of other risk factors.

These questions, concerning the interplay of genetics and environment are important to work going on now to find ways to prevent the onset of LHON,and may well be of importance to furthering research in other optic nerve diseases, and neurodegenerative diseases.

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