Dominant inheritance

Mutations in two genes directly lead to a disease. Mutations in the AQPO gene lead to dominantly inherited cataract. Single amino acid substitution in the AQPO gene in both mice and humans result in proteins with impaired trafficking to the plasma membrane and cataract formation, due to loss of the integrity of the lens. 

Mutations in GK (Hx IV) causes maturity-onset diabetes of the young (MOD Y), a form of non-insulin-dependent diabetes mellitus (NIDDM) characterized by onset before 25 years of age and an autosomal dominant inheritance (PI 2). This suggests that the mutations in other forms of Hx may also contribute to the development of NIDDM. Among them, Hx II is a particularly attractive candidate, although this isozyme is not expressed in red blood cells. Hx II has been analyzed extensively in the muscle of prediabetic insulin-resistant individuals. But studies have shown that Hx II mutation alone is unlikely to have a significant role in the development of peripheral insulin resistance and NIDDM (L6). 

Familial hypercholesterolemia (FH) is an autosomal dominantly inherited disease caused by mutations in the gene for the LDL receptor. Up to now more than 680 distinct mutations, distributed over the entire gene, have been described [42]. Heterozygous FH individuals express only half the number of functional LDL-r and, therefore, have a markedly raised plasma cholesterol and usually present with premature coronary artery disease. Homozygous FH individuals are more severely affected and may succumb before the age of maturity. The prevalence of heterozygous FH is approximately 1 in 500 in Caucasians. 

Acute intermittent porphyria is a dominantly inherited partial deficiency of porphobilinogen deaminase, and causes axonal polyneuropathy. Acute intermittent porphyria is caused by partial deficiency of porphobilinogen deaminase, an enzyme required for heme biosynthesis. Patients may present with acute abdominal pain, rapidly progressive sensorimotor axonal polyneuropathy or psychosis, and have elevated concentrations of the heme precursor 8-amino-levulinic acid in their urine. Symptoms may be precipitated by treatment with barbiturates or other drugs and are suppressed by treatment with hematin [59]. 

Lewy bodies, neurofibrillary lesions and Pick bodies are intracellular filamentous inclusions. It is now well established that Lewy bodies are made of the protein a-synuclein and both neurofibrillary lesions and Pick bodies of the microtubule-associated protein tau. Mutations in the a-synuclein gene or an increase in its copy number cause autosomal-dominantly inherited forms of Parkinson s disease and dementia with Lewy bodies. Mutations in the tau gene cause a familial form of frontotemporal dementia. Here we review the evidence implicating a-synuclein and tau in these inherited and a number of sporadic neurodegenerative diseases. Collectively, a-synucleinopathies and tauopathies account for the vast majority of cases of late-onset neurodegenerative disease (Tables 45-1 and 45-2). 

FIGURE 45-2 Missense mutations in the a-synuclein gene and multiplication of the chromosomal region containing the a-synuclein gene cause autosomal-dominantly inherited forms of Parkinson s disease and dementia with Lewy bodies. The a-synuclein gene is shown schematically in green. 

Frontotemporal dementias occur as familial forms and, more commonly, as sporadic diseases. They are characterized by a remarkably circumscribed atrophy of the frontal and temporal lobes of the cerebral cortex, often with additional, subcortical changes. In 1994, an autosomal-dominantly inherited form of frontotemporal dementia with parkinsonism was linked to chromosome 17q21.2. Subsequently, other forms of frontotemporal dementia were linked to this region, resulting in the denomination frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) for this class of disease. All cases of FTDP-17 have so far shown a filamentous pathology made of hyperphosphorylated tau protein (Fig. 45-7). In 1998, mutations in tau were reported in FTDP-17 patients [29-31]. Since then, more than 30 different mutations have been described in over 80 families with FTDP-17 (Fig. 45-6). 

Autosomal dominant inheritance A person affected by an autosomal dominant disorder has a 50 percent chance of passing the mutated gene to each child. The chance that a child will not inherit the mutated gene is also 50 percent. 

X-linked dominant inheritance The chance of passing on an X-linked dominant condition differs between men and women because men have one X chromosome and one Y chromosome, while women have two X chromosomes. A man passes on his Y chromosome to all of his sons and his X chromosome to all of his daughters. Therefore, the sons of a man with an X-linked dominant disorder will not be affected, but all of his daughters will inherit the condition. A woman passes on one or the other of her X chromosomes to each child. Therefore, a woman with an X-linked dominant disorder has a 50 percent chance of having an affected daughter or son with each pregnancy. 

Mutations in both the NC and collagenous domains of COL6A1, COL6A2, or COL6A3 cause Bethlem myopathya dominantly inherited disorder. Ulrich congenital muscular dystrophy can be caused by... 

Affected females often have more mild and variable symptoms than affected males. There are very few diseases with X-linked dominant inheritance. 

A number of features in a pedigree help to identify autosomal dominant inheritance ... 

As in autosomal dominant inheritance, the disease phenotype is seen in multiple generations of a pedigree skipped generations are relatively unusual. 

Figure II-1-9 shows the recurrence risks for X-linked dominant inheritance.

Figure 11-1-9. Recurrence Risks for X-Linked Dominant Inheritance...

X-Iinked dominant inheritance (choice D) is excluded because affected males can transmit X-linked dominant mutations to their daughters. 

The other modes of inheritance can influence the relative proportions of affected individuals who belong to one gender or the other (e.g., more affected males under X-linked recessive inheritance, more affected females under X-linked dominant inheritance), but they do not involve any differences in expression depending on the transmitting parent. 

Hirata, T., Kakizuka, A., Ushikubi, F., Fuse, I., Okuma, M., and Narumiya, S. (1994) Arg60 to Leu mutation of the human thromboxane A receptor in a dominantly inherited bleeding disorder. J. Clin. Invest. 94, 1662-1667. 

Huntington s chorea is a rare, dominantly inherited, progressive disease characterised by chorea (brief involuntary jerky muscle contractions) and dementia. It has an insidious onset and usually occurs between 30 and 50 years of age. Symptoms include uncontrolled movements, personality disorders, severe depression and anxiety. 

Figure 13-2. Pedigrees illustrating autosomal inheritance patterns. Recessive inheritance is shown in pedigrees A and B. Note that consanguinity in pedigree B reinforces the hypothesis of an autosomal recessive disorder. Dominant inheritance is shown in pedigree C, in which every affected person has an affected parent.

B. In autosomal dominant inheritance, the condition is expressed even if a single... 

These genetic diseases are examples of the various molecular explanations for dominant inheritance. 

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