Combined effect causes complicated HSP
That HSP turns out differently in different family members is no surprise as the experience is very common. Differences in age of onset, symptom severity, type and range of symptoms, and rate of progression commonly occur in people with identical mutations, and even in the same family.
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How can this be explained? The conclusion of the two studies below into reduced age at onset is that the particular mutation type extends into, and affects the gene next to it, compounding the effects of the HSP gene, leading to reduced age at onset.
Abstract
Many genetic neurological disorders exhibit variable expression within affected families, often exemplified by variations in disease age at onset.
Epistatic effects (i.e. effects of modifier genes on the disease gene) may underlie this variation, but the mechanistic basis for such epistatic interactions is rarely understood. Here we report a novel epistatic interaction between SPAST and the contiguous gene DPY30, which modifies age at onset in hereditary spastic paraplegia, a genetic axonopathy.
We found that patients with hereditary spastic paraplegia caused by genomic deletions of SPAST that extended into DPY30 had a significantly younger age at onset. We show that, like spastin, the protein encoded by SPAST, the DPY30 protein controls endosomal tubule fission, traffic of mannose 6-phosphate receptors from endosomes to the Golgi, and lysosomal ultrastructural morphology. We propose that additive effects on this pathway explain the reduced age of onset of hereditary plastic paraplegia in patients who are haploinsufficient for both genes.
SOURCE: Brain. 2018 May 1;141(5):1286-1299. doi: 10.1093/brain/awy034. PMID: 29481671
Mechanistic basis of an epistatic interaction reducing age at onset in hereditary spastic paraplegia.
Newton T1, Allison R1, Edgar JR2, Lumb JH1, Rodger CE1, Manna PT2, Rizo T3, Kohl Z4, Nygren AOH5, Arning L6, Schüle R7,8, Depienne C9,10, Goldberg L11, Frahm C12, Stevanin G9,10,13, Durr A9,10, Schöls L7,8, Winner B4, Beetz C11, Reid E1.
1 Department of Medical Genetics and Cambridge Institute for Medical Research, University of Cambridge, UK.
2 Department of Clinical Biochemistry and Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, UK.
3 Department of Stem Cell Biology, Friedrich-Alexander University Erlangen-Nuernberg (FAU), Erlangen, Germany.
4 Department of Molecular Neurology, Friedrich-Alexander University Erlangen-Nuernberg (FAU), Erlangen, Germany.
5 MRC-Holland, Amsterdam, The Netherlands.
6 Department of Human Genetics, Ruhr-University, Bochum, Germany.
7 Center for Neurology and Hertie Institute for Clinical Brain Research, Eberhard-Karls-University, 72076 Tübingen, Germany.
8 German Center of Neurodegenerative Diseases (DZNE), 72076 Tübingen, Germany.
9 ICM Brain and Spine Institute, INSERM U1127, CNRS UMR7225, Sorbonne Universites, UPMC Univ Paris VI UMR_S1127, Paris, France.
10 APHP, Genetic Department, Pitie-Salpêtrière University Hospital, Paris, France.
11 Department of Clinical Chemistry and Laboratory Diagnostics, Jena University Hospital, Jena, Germany.
12 Hans Berger Department of Neurology, Jena University Hospital, Jena, Germany.
13 Ecole Pratique des Hautes Etudes, PSL Research University, Paris, France.
2010 study of a Japanese family with SPAST HSP that identified for the first time the association with a mutation in adjacent gene DPY30.
Abstract
Spastic paraplegia type 4 (SPG4) is the most common autosomal dominant hereditary SPG caused by mutations in the SPAST gene.
We studied the four-generation pedigree of a Japanese family with autosomal dominant hereditary SPG both clinically and genetically. Twelve available family members (ten affected; two unaffected) and two spouses were enrolled in the study.
The clinical features were hyperreflexia in all four limbs, spasticity of the lower extremities, impaired vibration sense, mild cognitive impairment confirmed by the Wechsler Adult Intelligence Scale-Third Edition, and peripheral neuropathy confirmed by neurophysiological examinations. All four female patients experienced miscarriages. The cerebrospinal fluid tau levels were mildly increased in two of three patients examined.
Linkage analyses revealed the highest logarithm of odds score of 2.64 at 2p23-p21 where the SPAST gene is located. Mutation scanning of the entire exonic regions of the SPAST gene by direct sequencing revealed no mutations. Exonic copy number analysis by real-time quantitative polymerase chain reaction revealed heterozygous deletion of exons 1 to 4 of the SPAST gene. Breakpoint analysis showed that the centromeric breakpoint was located within intron 4 of SPAST while the telomeric breakpoint was located within intron 3 of the neighboring DPY30 gene, causing a deletion of approximately 70 kb ranging from exons 1 to 3 of DPY30 to exons 1 to 4 of SPAST.
To our knowledge, this is the first report of SPG4 associated with partial deletions of both the SPAST and DPY30 genes. The partial heterozygous deletion of DPY30 could modify the phenotypic expression of SPG4 patients with this pedigree.
SOURCE: Neurogenetics. 2011 Feb;12(1):25-31. doi: 10.1007/s10048-010-0260-7. Epub 2010 Sep 22. PMID: 20857310
Partial SPAST and DPY30 deletions in a Japanese spastic paraplegia type 4 family.
Miura S1, Shibata H, Kida H, Noda K, Toyama T, Iwasaki N, Iwaki A, Ayabe M, Aizawa H, Taniwaki T, Fukumaki Y.
1 Division of Respirology, Neurology and Rheumatology, Department of Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka, 830-0011, Japan. [email protected]