TTR fibrils share common heart structure in ATTR amyloidosis

Researchers have identified a common structure among toxic transthyretin (TTR) clumps, called amyloid fibrils, in heart tissue from people carrying mutations linked to hereditary transthyretin amyloidosis with polyneuropathy (hATTR-PN).

Such structural similarity contrasts with previous reports of structural variability among heart amyloid fibrils from other primarily polyneuropathic forms of hereditary ATTR amyloidosis. The results suggest that amyloid fibril architecture alone may not fully explain the clinical diversity in ATTR amyloidosis, a group of diseases that includes hATTR-PN.

“This structural consistency is significant for the development of structure-guided diagnostic tools capable of addressing the diverse spectrum of ATTR amyloidosis,” the researchers wrote.

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Study looks at TTR fibril structure

The findings were described in the study “A shared amyloid fold in cardiac fibrils from three neuropathy-associated ATTR variants,” published in Structure by a team led by researchers in the U.S.

ATTR amyloidosis is a group of diseases in which the TTR protein, mainly produced in the liver, misfolds and accumulates in tissues and organs as amyloid fibrils, or rope-like protein clumps, causing damage.

There are two main types of ATTR amyloidosis. The so-called wild-type form (wtATTR) develops with age, and amyloid fibrils mainly build up in the heart, causing heart disease (cardiomyopathy, or CM). Hereditary ATTR amyloidosis (hATTR), meanwhile, is caused by inherited mutations in the TTR gene.

Depending on the disease-causing mutation, hATTR can mainly cause nerve damage (polyneuropathy), cardiomyopathy, or a combination of both, but patients carrying the same TTR mutation can have very different symptoms. However, the reasons for this are not well understood.

Previous research using cryo-electron microscopy (cryo-EM), a technique that generates highly detailed images of protein structures, has shown that most amyloid fibrils in the heart of wtATTR patients share a single, predominant shape referred to as the “closed-gate” conformation. This structure features a polar channel (a water-attracting tunnel) that runs directly through the core of the fibril.

Prior work showed mixed fibril patterns

Heart amyloid fibrils from hATTR patients carrying certain TTR mutations, including Val30Met (the most common hATTR-PN-causing mutation) and Val122Ile (the most common cause of hereditary ATTR-CM in the U.S.), “also share a similar conformation to ATTRwt fibrils,” the researchers wrote. “These patients typically present with cardiomyopathy or a combination of cardiomyopathy and polyneuropathy.”

However, previous work by the team of researchers showed that two TTR mutations associated mainly with polyneuropathy, called Ile84Ser and Val122del, were linked to heart amyloid fibrils with additional structural variations.

“Whether these structural differences are associated with [clinical] variation between cardiomyopathy and polyneuropathy in patients with [hATTR] requires further investigation,” the researchers wrote.

To investigate this, the team studied amyloid fibrils extracted from the hearts of three patients carrying TTR mutations linked to hATTR-PN, each with a different mutation: Pro24Ser, Ala25Ser, and Asp38Ala.

“We aim to elucidate a potential link between [polyneuropathy symptoms], distinct mutations, and amyloid structural diversity,” the researchers wrote.

Patients had varied symptoms

All three patients had polyneuropathy, but their clinical presentations differed considerably. The patient carrying the Pro24Ser mutation had peripheral neuropathy, cardiomyopathy, and carpal tunnel syndrome, a nerve condition that can cause numbness and tingling in the affected hand.

The patient with the Ala25Ser mutation experienced a rapid-onset polyneuropathy beginning within days of an influenza vaccination, progressing to severe symptoms within two years. The patient carrying the Asp38Ala mutation had severe polyneuropathy and underwent a liver transplant, which was followed by rapidly progressive heart involvement requiring a heart transplant.

Protein analysis confirmed that heart samples from all three patients contained type A fibrils, which consist of a mixture of full-length TTR protein and smaller protein fragments. Further tests showed that the fibrils contained both normal and mutant TTR, consistent with each patient carrying one mutant and one normal copy of the TTR gene.

The team also examined where the fibril proteins were cut by enzymes. Fibrils from all patients shared a common set of cut sites, with some additional sites unique to each variant. The analysis identified these cut sites, but not when the cuts occurred.

Cryo-EM imaging and structural analysis revealed that fibrils from all three patients adopted the same closed-gate conformation observed in wtATTR and in most previously studied hATTR heart fibrils.

Heart fibrils shared common structure

Structural comparisons between fibrils derived from the Pro24Ser and Asp38Ala mutations revealed similar stabilities to those previously published for ATTRv and wtATTR fibril structures.

While prior studies have found liver-derived amyloid fibrils with similar structures across tissues, the team emphasized that because the amyloid fibrils were extracted exclusively from heart tissue, conclusions cannot be made about fibrils in nerves or other organs.

“Our data reinforce a central observation: [hATTR heart] fibrils adopt a remarkably conserved fold across mutations and clinical presentations,” the researchers wrote. “Whether this [similarity] itself influences disease course, or whether subtler, localized [differences] play a role, remains to be clarified.”