A clinical, molecular genetics and pathological study of a FTDP-17 family with a heterozygous splicing variant c.823-10G>T at the intron 9/exon 10 of the MAPT gene

Diana A Olszewska,Conor Fearon,Christopher Mcguigan,Terri P Mcveigh,Henry Houlden,James M Polke,Brian Lawlor,Robert Coen,Michael Hutchinson,Michael Hutton,Alan Beausang,Isabelle Delon,Francesca Brett,Ioanna Sevastou,Nuria Seto-Salvia,Rohan De Silva,Tim Lynch

doi:10.1016/j.neurobiolaging.2021.05.010

Abstract

We report the first clinical-radiological-genetic-molecular-pathological study of a kindred with c.823-10G>T MAPT intronic variant (rs63749974) associated with frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). We describe the clinical spectrum within this family and emphasize the association between MAPT gene variants and motor neuron disease. This report of a second family with FTDP-17 associated with c.823-10G>T MAPT variant strongly supports pathogenicity of the variant and confirms it is a 4-repeat (4R) tauopathy. This intronic point mutation, probably strengthens the polypyrimidine tract and alters the splicing of exon 10 (10 nucleotides into intron 9) close to the 3’ splice site.

Highlights

In 1994, we reported an Irish-American family with frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) and termed this disorder disinhibition-dementiaparkinsonism-amyotrophy-complex (DDPAC) (Lynch et al, 1994; Wilhelmsen et al, 1994; Sima et al, 1996)
We present the first pathological study of a c.823-10G>T variant family, confirming that this variant results in altered microtubule-associated protein tau gene (MAPT) exon 10 splicing leading to increased 4R tau and provide supportive evidence of pathogenicity of c.823-10G>T
In the adult human brain, there are six tau isoforms distinguished by the presence or absence of 29 and 58 amino acids in the MAPT amino-terminal half and a 31 amino-acid repeat domain in the MAPT carboxy-terminal half encoded by exon 10 (Goedert et al 1989, Spillantini et al 1997, Hasegawa et al 1998, Hong et al 1998)

Summary

Introduction

In 1994, we reported an Irish-American family with frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) and termed this disorder disinhibition-dementiaparkinsonism-amyotrophy-complex (DDPAC) (Lynch et al, 1994; Wilhelmsen et al, 1994; Sima et al, 1996). This led to a clinical-radiological-pathological-genetic linkage study and ultimate cloning of the microtubule-associated protein tau gene (MAPT) on chromosome 17q21.31 (Hutton et al, 1998; Spillantini et al, 1998). Variants in MAPT are responsible for 15-20% of hereditary frontotemporal lobar degeneration (FTLD). McGuigan et al / Neurobiology of Aging 106 (2021) 343.e343–343.e8

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