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,

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