HTT – Huntington Disease

Huntington disease (Huntington disease, HD) is an autosomal dominant neurodegenerative disorder characterized by progressive motor dysfunction, cognitive decline, and psychiatric disturbances. The disease results from CAG trinucleotide repeat expansions in the HTT gene (HTT), on chromosome 4p16.3. Clinical onset typically occurs in mid-adulthood; larger repeat expansions correlate with earlier onset. Prevalence is approximately 5–10 per 100 000 in populations of European descent.

Genetic evidence for the HTT–HD association is definitive. Molecular screening in 626 Brazilian HD patients confirmed expanded alleles (43–73 CAG repeats) in 25 unrelated families, with 76% of probands affected (CAG≥36) [PMID:10770860]. Segregation analysis in five multiplex pedigrees demonstrated perfect co-inheritance of pathogenic expansions with disease across multiple generations [PMID:7898693]. Cases of de novo CAG expansions and rare biallelic mutations further support the repeat-expansion mechanism.

The variant spectrum is dominated by CAG repeat expansions of varying lengths. Pathogenic expansions range from reduced penetrance alleles (36–39 repeats) to juvenile-onset expansions (>100 repeats). Intermediate alleles (27–35 repeats) can undergo intergenerational expansion, particularly via paternal transmission, leading to full-penetrance mutations in offspring. No other coding or splice variants in HTT have been linked to HD.

Functional studies demonstrate that N-terminal fragments of mutant huntingtin undergo aberrant proteolytic cleavage, mislocalize, and form toxic aggregates. Caspase-3 cleavage produces N-terminal fragments that preferentially associate with membranes and seed aggregate formation [PMID:11675509]. Mutant fragments sequester transcription factors, suppress BDNF expression, and disrupt CREB signaling in astrocytes [PMID:22234237]. Aggregates also impair mitochondrial function and proteasomal activity.

Animal and cellular models recapitulate HD pathology. Transgenic mice expressing N-terminal htt exon-1 fragments with expanded polyglutamine tracts (N171–82Q) develop neuronal inclusions, motor deficits, and premature death, paralleling human disease phenotypes [PMID:15190011]. Full-length and longer N-terminal constructs show attenuated transcriptional changes, suggesting fragment length modulates pathogenic impact.

In summary, HTT CAG repeat expansion is the definitive cause of HD, supported by robust genetic segregation, a clear variant spectrum, and concordant functional and animal model data. Molecular diagnosis via CAG sizing informs prognosis and enables genetic counseling. Allele-specific therapeutic strategies targeting mutant HTT are under active development.

References

• Arquivos de neuro-psiquiatria • 2000 • Molecular diagnosis of Huntington disease in Brazilian patients. PMID:10770860
• Neurology • 1995 • Hereditary late-onset chorea without significant dementia: genetic evidence for substantial phenotypic variation in Huntington's disease. PMID:7898693
• Human Molecular Genetics • 2004 • Nuclear-targeting of mutant huntingtin fragments produces Huntington's disease-like phenotypes in transgenic mice. PMID:15190011
• Proceedings of the National Academy of Sciences of the United States of America • 2001 • Caspase 3-cleaved N-terminal fragments of wild-type and mutant huntingtin are present in normal and Huntington's disease brains, associate with membranes, and undergo calpain-dependent proteolysis. PMID:11675509
• Acta biochimica et biophysica Sinica • 2012 • Truncated N-terminal huntingtin fragment with expanded-polyglutamine (htt552-100Q) suppresses brain-derived neurotrophic factor transcription in astrocytes. PMID:22234237

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