Question

Develop a case study/report on the Huntington disease and the gene for this disease is HTT gene. When you are developing the case study, start it from the DNA variant(a specific variant of the HTT gene) to the phenotype of the diseased patient.

The case report you should include the following:

1) Description of genomic/epigenomic/cytogenetic/transcriptomic/proteomic characterization/detection of disease (how is the genetic cause determined)

2) Give a flow chart for determination of the genetic cause at the clinical level (i.e. phenomic upon the first presentation to the clinic to confirmation of genetic disorder).

3) Draw a three-generation pedigree with at least 15 family members.

4) A narrative describing the pedigree of the disease.

Answer 1

Huntington disease is a neurological disease that leads to progressive degeneration or the progressive breakdown of nerve cells of brain cells, which in turn cause severe muscle spasm and personality disorders. It causes uncontrolled movements, emotional problems, and loss of thinking ability (cognition). Huntington disease caused by the mutation of the gene huntingtin (htt) which codes for a protein called the huntingtin protein. The HD gene is located on the short (p) arm of chromosome 4 at position 16.3, from 3,074,510 bp to 3,243,960 bp. The gene contains many repeats of the base triplet AGC (Adenine, Guanine, Cytosine) called a “triplet repeat” or “trinucleotide repeat”. Normal persons have 11 to 34 copies of the triplet and affected persons tend to have 42 to more than 120 copies. The varients of HTT gene are c.52_54CAG[9_26] (≤26 CAG repeats), c.52CAG[27_35] (27 to 35 CAG repeats) (Benign), c.52CAG[36_39] (36 to 39 CAG repeats), c.52CAG[40_?]  (≥40 CAG repeats) (Pathogenic).

HD is a neurodegenerative disease caused by an unstable expanded CAG repeats in the HTT, which results in the production of mutant protein (mHtt) with a toxic polyglutamine (polyQ) tract. Since polyQ expansion toxicity is correlated with repeat size ie., longer CAG expansions are more severely affected. HD is characterized by a primary degeneration of two structures of the basal ganglia: the caudate nucleus and the putamen that form the neostriatum. PolyQ-Htt presents a high propensity to misfold and aggregate, which leads to the formation of nuclear inclusions, particularly in neurons. These aggregates, a disease hallmark, recruit a number of proteins, including transcriptional regulators.

In HD transcriptional changes are progressive, CAG repeat-length-dependent and most extended in the striatum. In the striatum of HD indivisuals, transcriptional changes occur in both directions: many genes are down- and up-regulated. The down- and up-regulated genes in HD brain tissues display distinct functional signatures. The mutant Htt-induced transcriptional effects are thought to involve both altered regulation of transcription regulators and histone-modifying enzymes.

Huntington’s disease is an autosomal dominant NDD characterized by neuropsychiatric and motor impairments caused by a CAG repeat expansion in exon 1 of the HTT gene, which leads to an expanded polyglutamine (polyQ) stretch in the N terminus of the huntingtin protein. A hallmark of this disorder is the appearance of cytoplasmic and intranuclear huntingtin (protein) aggregates, which interfere with several cellular processes, such as vesicular trafficking, transcription, proteostasis and energy metabolism. Aggregation of polyglutamine-expanded huntingtin exon 1 (HttEx1) in Huntington’s disease (HD) proceeds from soluble oligomers to late-stage inclusions.