Autosomal dominant disorders

The autosomal dominant disorders follow autosomal dominant inheritance. A dominant gene expresses itself even in a single dose. It affects both the sexes and the affected individual always has an affected parent. However, if both the parents show the trait, 25% of the progeny gets severely affected. The autosomal dominant trait does not skip the generations. Following are some common examples of autosomal dominant disorders.

Huntington’s disease:

It affects the movements of the individuals leading to jerks and muscle twitches. The disorder affects the middle-aged people. Involuntary movements of the face, hands, and legs occur commonly in these individuals. The disorder also affects speech and intellectual capabilities. It leads to progressive cell death in the central nervous system. This type of autosomal dominant disease affects 1 in 15,000 individuals. It also results in dementia, loss of memory, and poor concentration. Huntington’s disease usually affects a person in the middle-age. However, some people show the symptoms before the age of 20. Such a disease is known as juvenile Huntington’s disease. The first symptom involves stiffness and clumsiness in the arms and legs. The speech and behavioral changes are also commonly found. 
Huntington’s disease is a progressive disorder. The symptoms increase with time and require a lot of support and care from the family members or the caretakers. Hence, Huntington’s disease consists of three main disorders such as movement disorders, cognitive disorders, and behavioral disorders. The symptoms vary in different individuals. Huntington disease affects the people in the same family. Most of them do not recover even after the treatment. Individuals with Huntington’s disease experience unexpected bodily movements, difficulty in working, cognitive impairment, and behavioral changes. These individuals exhibit difficulty in planning and execution. They show behavioral changes. Sometimes, it becomes difficult to diagnose Huntington’s disease.

Image 1: Huntington's disease

Genetics:

A mutated gene present on chromosome number 4 contains an abnormally large nucleotide repeat. It is known as CAG nucleotide and is present at the 5’ end. The gene present on the chromosome 4 encodes a protein known as Huntingtin. It is responsible for neuronal cell apoptosis. It typically gets inherited from the affected parent(s). The CAG nucleotide gets repeated multiple times leading to a polyglutamine tract. The CAG is a triplet codon since it contains three bases such as cytosine, adenine, and guanine. Hence, it is responsible for coding an amino acid known as glutamine. Huntington’s disease mainly involves an altered HTT gene. It passes from generation to generation. Hence, it involves no skipping of generations. The CAG trinucleotide repeat increases in the size. Hence, a very large number of CAG repeats get involved in this progressive disorder. A phenomenon known as anticipation involves observing the number of CAG repeats for studying the signs and symptoms of the disease. There is a specific number of trinucleotide repeat for each type of Huntington’s disease. The adult-onset form of the Huntington’s disease anticipates 40 to 50 CAG repeats in the HTT gene. Individuals with the juvenile Huntington’s disease show the presence of more than 60 CAG repeats. Low-risk individuals with 25-35 CAG repeats do not develop the disease. However, their children may get the disease. Passing the gene from one generation to the next may increase the length of the CAG repeat.

Myotonic dystrophy:

It mostly affects the adults. Myotonic dystrophy is a progressive muscle weakening disorder. Mainly, the hands, neck, lower legs, and the facial muscles become weak. The word myotonia indicates a tonic spasm of the muscles. It not only affects the muscles but also affects the working capacity of an individual, the movements and the speech. Prolonged muscle contractions or myotonia is a common feature of this condition. It also accompanies hypotonia and clubfoot. Since heart consist of muscle tissue, individuals with myotonic dystrophy also suffer from heart problems. They experience cardiac conduction defects. They have abnormalities related to electrical signals and heartbeats. Ophthalmic disorders are also common among them. Most of the affected men are infertile. Individuals start experiencing the symptoms in their twenties or thirties. The trait does not skip the generations. There are two types of myotonic dystrophies such as type 1 and type 2 myotonic dystrophies. Type 1 myotonic dystrophy shows aggressive symptoms. Type 2 myotonic dystrophy is a milder one. They also experience circulatory, respiratory, and gastrointestinal problems. This type of autosomal dominant disorder affects 1 in 8000 people.

·        Genetics

There is a gene known as DMPK gene which gets mutated. It is an unstable region with a progressive increase in its length. One more gene associated with increased length is known as the CNBP gene. One copy of the altered DMPK gene or a CNBP gene is enough to progress the muscle weakness. At least one parent of the proband must be affected. The DMPK gene encodes a protein involved in cellular communication and signaling. It helps in muscle function. The CNBP gene produces a protein responsible for controlling the heart and the skeletal muscles. Alterations in the DMPK and CNBP genes cause myotonic dystrophies. Abnormal repetition of the gene segment known as CTG triplet repeat sequence mainly results in the weakened muscles due to improper protein products. Since DNA gets transcribed into mRNA and mRNA gets translated into a protein, abnormally large DNA with repetitive segments leads to an expanded form of mRNA. The expanded mRNA finally translates a faulty protein product. The abnormal mRNA also interferes with the other proteins resulting in clumps. A combined effect of all the above factors such as gene mutations, abnormally long DNA segments, clumps due to extended RNA, and faulty protein products lead to muscle weakening and dystrophy.

Familial hypercholesterolemia:

It arises due to defective LDL receptors. The cholesterol gets deposited in the arteries and causes myocardial infarction (heart attacks). This type of autosomal dominant disorder affects 1 in 500 people.

Image 2: Familial hypercholesterolemia

·        Genetics:

Familial hypercholesterolemia arises due to many gene mutations. However, the condition is autosomal dominant one. A most common gene mutation responsible for familial hypercholesterolemia is known as LDLR mutation. Other gene mutations include ApoB, PCSK9, and LDLRAP1 gene mutations. Some other gene alterations such as ABCG5 and ABCG8 may also lead to cholesterol depositions in the tissues. LDLR indicates Low-density lipoprotein receptor. LDLR gene mutations related to mutations in the LDLR gene encoding the LDL receptor protein. LDLR gene is present on the 19th chromosome. Heterozygosity or the presence of one copy of the abnormal gene is enough for causing the disease. Homozygotes experience cardiovascular problems since childhood. There are five major conditions associated with LDLR gene mutations. The conditions include improper synthesis of LDLR, inefficient transport of the receptor protein from the endoplasmic reticulum to the Golgi apparatus, lack of LDLR binding to the LDL, improper clustering, and no recycling of the LDLR to the cell surface.

Achondroplasia:

It leads to dwarfism. Such individuals show normal intelligence and reproductive ability. This type of autosomal dominant disorder affects 1 in 10,000 people. The main feature of Achondroplasia is dwarfism. The individuals with dwarfism show the disproportionate body, short limbs, large head with a small facial size, a flat nasal bridge, and affected spinal curvature.

·        Genetics:

A gene known as fibroblast growth factor receptor 3 (FGFR3) gene gets altered. It negatively gets regulated causing bone defects. The FGFR3 gene encodes a protein involved in bone health and development. The result of the altered FGFR3 gene is an overly active protein. It does not allow proper development of the bones and the skeleton. It also interferes with bone maintenance and growth. Hence, these individuals are abnormally short. One copy of the mutant FGFR3 gene is enough for the condition to occur. The presence of two copies of the mutant gene proves fatal. It is not only an autosomal dominant disorder but also a result of spontaneous mutations. New gene mutation gets inherited due to an imbalance in the spermatogenesis in the father.

Neurofibromatosis:

It occurs due to complete penetrance and variable expression. This type of autosomal dominant disorder leads to tumourous outgrowths on the skin accompanying epilepsy. It also exhibits Macrocephaly or an abnormally large head. Neurofibromatosis type 1 leads to changes in the skin pigmentation and tumorous outgrowths in the nerves and the brain. Neurofibromatosis type 2 leads to noncancerous tumors in the nervous system.

·        Genetics:

The mutant gene responsible for neurofibromatosis is present on the long arm of chromosome number 14. The gene helps in synthesizing a protein known as neurofibromin. The gene acts as a tumor suppressor gene. However, abnormality or the alteration in this gene causes benign tumors on the skin. Loss of both the alleles leads to the development of the tumor. There are two types of neurofibromatosis such as NF-1 and NF-2. People with NF-1 have NF-1 gene mutations leading to an autosomal dominant condition. NF-2 gene mutations lead to Neurofibromatosis type-2. 

References:
[1] Medical genetics, G.P. Pal
[2] Human Genetics, 3/e, Gangane
[3] Vogel and Motulsky's Human Genetics: Problems and Approaches, Friedrich Vogel, Gunter Vogel, Arno G. Motulsky
[4] Biology for the IB Diploma: Standard and Higher Level, Andrew Allott
[5] Principles of Medical Genetics, Thomas D. Gelehrter,

© Copyright, 2018 All Rights Reserved.

Autosomal dominant inheritance

There are total 22 pairs of autosomes in humans. The non-sex chromosomes are known as autosomes. The anomalies associated with the autosomes are known as autosomal anomalies or autosomal abnormalities. The mutations in the genes present on these autosomes decide the inheritance of a particular disease. An autosome consists of a mutant gene in autosomal disorders. The mutant gene expresses the disorder even though present in a single dose. Autosomal diseases involve the presence of a mutant gene on one of the chromosomes in a pair. Consider a mating between a normal individual and an affected individual. The normal individual has a normal genotype. The affected individual has a mutant gene. Hence, 50% of the progeny will express the dominant mutant gene. The remaining 50% of progeny will be normal. The individuals showing a dominant mutant gene are known as heterozygotes. Consider another case of mating between both the affected parents. 25% of the offspring will show both the mutant genes. Hence, they are known as severely affected individuals. 50% of the progeny will show one mutant gene. Hence, they are known as affected individuals. The remaining 25% of individuals show a normal genotype.

Following are the characteristics of an autosomal dominant inheritance:

1.     Both the sexes equally get affected with the autosomal dominant traits.

2.    The genes or the traits get transmitted in four possible ways such as male to male, male to female, female to female and female to male types of transmissions. 

3.    Follows no skipping of generations

4.    Mostly seen in all the generations

5.    In most of the cases, the proband has at least one affected parent

6.    New autosomal dominant mutations occur newly in a generation due to some error in the gametogenesis in the parent. The child having new mutations passes on the traits to the next generations

7.   Those having the abnormal genes on the autosomes only pass on the trait to the next generation

8.  Those having normal genes and exhibiting normal phenotype do not pass on the trait

9.  The proportion of the normal and the affected individuals in a population is almost the same.

10.  An autosomal dominant gene mostly affects one part of the body. However, it may also lead to a disorder where many parts of the body get affected. One mutated gene can affect many phenotypes. A phenomenon in which one gene produces many phenotypes is known as pleiotropy. Hence, the autosomal dominant gene may exhibit pleiotropy.

11. The expression of the autosomal dominant gene varies from person to person. The phenotype also varies.

12. Sometimes a heterozygous individual does not show or express the dominant phenotype. Such a condition is known as penetrance. It occurs due to the influence of the genes at other loci.

Image: Autosomal dominant inheritance

Following are the examples of autosomal dominant disorders

Huntington’s chorea:

It involves a complete penetrance. Such a type of autosomal dominant disorder leads to nerve cell death and affects the central nervous system. It is a movement disorder mainly known to affect a person in the middle age. Hence, this type of movement is known as chorea. The mutated gene is present on the short of the 4^th chromosome. The gene shows the presence of an abnormally large CAG nucleotide repeat at 5’ end. A series of CAG repeats result in the production of glutamine chains. A glutamine chain is also known as a polyglutamine tract. This gene encodes Huntington protein. The altered form of Huntingtin protein is known as mutant Huntingtin. It increases the rate of neuronal cell death.  Huntington’s chorea affects 1 in 15,000 individuals. It leads to the breakdown of the nerve cells in the brain. Hence, such individuals experience a diminished ability to walk, speak, and carry out other activities. Involuntary movements in the face, muscles, hands, and legs occur in this condition. Jerks are very common in them. The intellectual ability also starts diminishing.

Familial hypercholesterolemia:

Familial hypercholesterolemia majorly involves heterozygous individuals and rarely involves homozygotes. Such a type of autosomal dominant disorder leads to high serum cholesterol level. Mutation in the LDL receptor gene leads to the disease. As the word suggests familial hypercholesterolemia, the defective gene gets inherited. The mutated gene responsible for the disease is present on chromosome number 19. An important clinical feature of familial hypercholesterolemia involves the progression of atherosclerosis. Cholesterol gets deposited in the arterial walls. Hence, it results in narrowing of the lumen. Three main types of cholesterols include LDL, HDL, and VLDL. LDL or low-density lipoprotein is known as bad cholesterol. HDL or high-density lipoprotein is also known as good cholesterol. Due to the defective LDL receptor, the patients suffering from familial hypercholesterolemia always show an increased level of blood cholesterol. The LDL cholesterol does not get eliminated from the blood. Xenthomata or the subcutaneous deposition of lipid occurs in familial hypercholesterolemia. Such individuals have an increased risk of myocardial infarction or heart attack. This type of autosomal dominant disorder affects 1 in 500 individuals.

Neurofibromatosis:

It shows complete penetrance and variable expression. The mutated gene is present on the 17^th chromosome. The gene encodes for neurofibromin protein. It is known as a tumor suppressor gene. A mutated tumor suppressor gene enhances the cancer cell growth. Loss of both the alleles leads to tumor development. Neurofibromatosis leads to pea-sized benign tumors on the skin. Apart from tumors, epilepsy also manifests. 1 in 3000 people suffers from neurofibromatosis.

Here are some more examples of Autosomal dominant disorders:

Examples of autosomal dominant disorders	Gene mutations
Myotonic dystrophy	An abnormal gene on the 19th chromosome with a large CTG repeats 3’ end.
Achondroplasia	An abnormal gene is present on the short arm of the 4th chromosome.
Polycystic kidney disease	Abnormal PKD1 gene on chromosome 16 and PKD2 gene on chromosome 4.
Congenital cataract	PITX3 gene mutation
Polydactyly	A mutated GLI 3 gene on the 7th chromosome

 Table: Autosomal dominant disorders and related gene mutations

Codominance:

Both the traits get expressed fully in the heterozygous state. Example of codominance involves ABO blood groups. Presence of both A and B alleles leads to codominance.

References:
[1] Medical genetics, G.P. Pal
[2] Human Genetics, 3/e, Gangane
[3] Vogel and Motulsky's Human Genetics: Problems and Approaches, Friedrich Vogel, Gunter Vogel, Arno G. Motulsky
[4] Biology for the IB Diploma: Standard and Higher Level, Andrew Allott
[5] Principles of Medical Genetics, Thomas D. Gelehrter,

© Copyright, 2018 All Rights Reserved.