A novel heterozygous variant in <i>ERLIN2</i> causes autosomal dominant pure hereditary spastic paraplegia

Rydning, Siri Lynne; Dudešek, Aleš; Rimmele, Florian; Funke, Claudia; Krüger, Stefanie; Biskup, Saskia; Vigeland, Magnus Dehli; Hjorthaug, Hanne Sagsveen; Sejersted, Yngve; Tallaksen, Chantal; Selmer, Kaja Kristine; Kamm, Christoph

doi:10.1111/ene.13625

Cited by 32 publications

(33 citation statements)

References 35 publications

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“…The vast majority of previous studies of ERLIN2 ‐related disorders have identified biallelic variants (Table S2). One report, however, identified a recurrent heterozygous missense variant (c.386G> C; p.Ser129Thr) in multiple affected individuals from two large unrelated families . Overall, these data lend support to the notion that there are autosomal‐recessive and autosomal‐dominant forms of ERLIN2 ‐related disorders, similar to a small number of other genetic causes of HSP, such as defects in ATL1 (SPG3A), KIF1A (SPG30), KIF1C (SPG58), REEP1 (SPG31), and SPG7 (SPG7) …”

Section: Discussionsupporting

confidence: 52%

“…The patient with the de novo heterozygous ERLIN2 variant (patient 5) appeared less severely affected compared to the other participants with homozygous ERLIN2 variants, as was shown by a later age of symptom onset, absence of developmental regression, and absence of ID. In fact, among prior reports of ERLIN2 ‐related disorders (Table 2), ID was absent in 5/6 unrelated individuals who had a missense ERLIN2 variant on at least one allele (three families with affected individuals); conversely, ID was present in all individuals with a homozygous truncating variant . This observation suggests that ERLIN2 ‐related disorders can present dosage‐dependent clinical features likely due to reduced protein function.…”

Section: Discussionmentioning

confidence: 78%

“…Affected individuals often present during infancy or childhood with delayed motor milestones and loss of motor abilities . Recently, an autosomal‐dominant form was described in two unrelated families with affected members carrying the same heterozygous missense variant in ERLIN2 (c.386G> C; p.Ser129Thr) . Finally, a homozygous splice junction variant causing reduced ERLIN2 transcript was the cause of juvenile primary lateral sclerosis in a consanguineous family with several members affected by language regression, pseudobulbar palsy, reduced muscle bulk, distal greater than proximal weakness, and kyphosis/scoliosis …”

Section: Introductionmentioning

confidence: 99%

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Expansion of the genetic landscape of ERLIN2‐related disorders

Srivastava

D’Amore

Cohen

et al. 2020

Ann Clin Transl Neurol

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ERLIN2-related disorders are rare conditions of the motor system and clinical details are limited to a small number of prior descriptions. We here presented clinical and genetic details in five individuals (four different families) where three subjects carried a common homozygous p.Asn292ArgfsX26, associated also with sensorineural hearing loss in one child. One further subject had a de novo p.Gln63Lys and one harbors the homozygous p.Val136Gly because of maternal isodisomy of chromosome 8. Overall, we expanded the clinical and genetic spectrum of ERLIN2-related disorders and we reiterate that autosomaldominant transmission is a potential mode of inheritance. Future research will elucidate disease mechanisms.

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Section: Discussionsupporting

confidence: 52%

Section: Discussionmentioning

confidence: 78%

Section: Introductionmentioning

confidence: 99%

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Expansion of the genetic landscape of ERLIN2‐related disorders

Srivastava

D’Amore

Cohen

et al. 2020

Ann Clin Transl Neurol

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“…Interestingly, mutations to erlin1 and, more commonly, erlin2 have been linked to rare neurodegenerative diseases; e.g. hereditary spastic paraplegia (7,(19)(20)(21)(22)(23)(24)(25)(26)(27). As yet, however, it has not been possible to define how the mutations affect the cell biological function of erlin2, or the erlin1/2 complex, and cause cell dysfunction (7).…”

Section: +mentioning

confidence: 99%

The erlin2 T65I mutation inhibits erlin1/2 complex–mediated inositol 1,4,5-trisphosphate receptor ubiquitination and phosphatidylinositol 3-phosphate binding

Wright

Bonzerato

Sliter

et al. 2018

Journal of Biological Chemistry

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The erlin1/2 complex is a ~2MDa endoplasmic reticulum membrane-located ensemble of the ~40kDa type II membrane proteins erlin1 and erlin2. The best-defined function of this complex is to mediate the ubiquitination of activated inositol 1,4,5-trisphosphate receptors (IP3Rs) and their subsequent degradation. However, it remains unclear how mutations of the erlin1/2 complex affect its cellular function and cause cellular dysfunction and diseases such as hereditary spastic paraplegia. Here, we used gene editing to ablate erlin1 or erlin2 expression to better define their individual roles in the cell and examined the functional effects of a spastic paraplegia-linked mutation to erlin2 (threonine to isoleucine at position 65; T65I). Our results revealed that erlin2 is the dominant player in mediating the interaction between the erlin1/2 complex and IP3Rs, and that the T65I mutation dramatically inhibits this interaction and the ability of the erlin1/2 complex to promote IP3R ubiquitination and degradation. Remarkably, we also discovered that the erlin1/2 complex specifically binds to phosphatidylinositol 3-phosphate, that erlin2 binds this phospholipid much more strongly than does erlin1, that the binding is inhibited by T65I mutation of erlin2, and that multiple determinants within the erlin2 polypeptide comprise the phosphatidylinositol 3-phosphate-binding site.Overall, these results indicate that erlin2 is the primary mediator of the cellular roles of the erlin1/2 complex and that disease-linked mutations of erlin2 can affect both IP3R processing and lipid binding.

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“…Family members highlighted in pink may benefit from cascade testing. 51 . The variant was also detected in his daughter (40s), currently without clinical manifestations.…”

Section: Medically Significant Genetic Findingsmentioning

confidence: 99%

Precision Medicine Advancements Using Whole Genome Sequencing, Noninvasive Whole Body Imaging, and Functional Diagnostics

Hou

Martin

et al. 2018

Preprint

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We report the results of a three-year precision medicine study that enrolled 1190 presumed healthy participants at a single research clinic. To enable a better assessment of disease risk and improve diagnosis, a precision health platform that integrates non-invasive functional measurements and clinical tests combined with whole genome sequencing (WGS) was developed. The platform included WGS, comprehensive quantitative non-contrast whole body (WB) and brain magnetic resonance imaging/angiography (MRI/MRA), computed tomography (CT) coronary artery calcium scoring, electrocardiogram, echocardiogram, continuous cardiac monitoring, clinical laboratory tests, and metabolomics. In our cohort, 24.3% had medically significant genetic findings (MSF) which may contribute to increased risk of disease. A total of 206 unique medically significant variants in 111 genes were identified, and forty individuals (3.4%) had more than one MSF. Phenotypic testing revealed: 34.2% of our cohort had a metabolomics profile suggestive of insulin resistance, 29.2% had elevated liver fat identified by MRI, 16.4% had clinically important cardiac structure or cardiac function abnormalities on cardiac MRI or ECHO, 8.8% had a high cardiovascular risk on CT coronary artery calcium scoring (Agatston calcium score > 400, Relative Risk of 7.2), 8.0% had arrhythmia found on continuous rhythm monitoring, 6.5% had cardiac conduction disorders found on EKG, 2% had previously undetected tumors detected by WB MRI, and 2.5% had previously undetected aneurysms detected by non-contrast MRI/MRA. Using family histories, personal histories, and test results, clinical and phenotypic findings were correlated with genomic findings in 130 study participants (63.1%) with high to moderate penetrance variants, suggesting the precision health platform improves the diagnostic process in asymptomatic individuals who were at risk. Cardiovascular and endocrine diseases achieved considerable clinical associations between MSFs and clinical phenotypes (89% and 72%, respectively). These findings demonstrate the value of integrating WGS and noninvasive clinical assessments for a rapid and integrated point-of-care clinical diagnosis of age-related diseases that contribute to premature mortality.

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A novel heterozygous variant in ERLIN2 causes autosomal dominant pure hereditary spastic paraplegia

Cited by 32 publications

References 35 publications

Expansion of the genetic landscape of ERLIN2‐related disorders

Expansion of the genetic landscape of ERLIN2‐related disorders

The erlin2 T65I mutation inhibits erlin1/2 complex–mediated inositol 1,4,5-trisphosphate receptor ubiquitination and phosphatidylinositol 3-phosphate binding

Precision Medicine Advancements Using Whole Genome Sequencing, Noninvasive Whole Body Imaging, and Functional Diagnostics

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