Motor Neurone Disease

Gene: PFN1

Green List (high evidence)

The association with ALS is well established, multiple families and different lines of functional data, including animal models support this association.

Agree, the evidence for association with a bone phenotype is moderate, the two families may well be related, supportive conditional mouse model. Different mechanism may be at play.

Created: 1 Oct 2020, 8:20 a.m. | Last Modified: 1 Oct 2020, 8:20 a.m.

Panel Version: 0.4720

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Amyotrophic lateral sclerosis 18, MIM# 614808

Publications

• 31802421
• 31611772
• 31401564
• 30203378
• 28040732
• 22801503

I don't know

A new phenotype association for this gene has been reported: Paget’s disease of bone (PDB).
Haploinsuffciency has been linked to PDB in 2 families with the same truncating frameshift variant (unsure if the families are related, both families are from the same region in Italy). Functional studies of this truncating variant showed abnormal protein aggregates (PMID: 32392277, 31991009). An osteoclast-specific conditional null mouse model confirmed the skeletal phenotype (PMID: 31346562). Missense variants in this gene have been previously associated with ALS (PMID: 22801503). Due to these different phenotype associations, it has been suggested that this gene can cause multisystem proteinopathy (PMID: 32589291).

Created: 1 Oct 2020, 6:09 a.m. | Last Modified: 1 Oct 2020, 6:09 a.m.

Panel Version: 0.4717

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Paget’s disease of bone

Publications

• 32392277
• 31991009
• 31346562
• 32589291
• 22801503

Green List (high evidence)

PMID: 23141414, PMID: 22801503, PMID: 25499087
- Total of 15 probands, all missense

*E117G (NM_005022.3) reported in 6 out of the 15 mentioned above and has 140 alleles in gnomAD
Suggested to be a risk factor instead (PMID: 24309268)

LoF and toxic GoF are suggested mechanisms, with functional studies demonstrating variants leading to insoluble aggregates (PMID: 22801503, PMID: 26908597)

Created: 1 Oct 2020, 5:52 a.m. | Last Modified: 1 Oct 2020, 5:52 a.m.

Panel Version: 0.111

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Amyotrophic lateral sclerosis 18 (MIM# 614808)

Publications

• 23141414
• 22801503
• 25499087
• 24309268
• 22801503
• 26908597