End‐Truncated <scp>LAMB1</scp> Causes a Hippocampal Memory Defect and a Leukoencephalopathy

Aloui, Chaker; Hervé, Dominique; Marenne, Gaëlle; Savenier, Florian; Guennec, Kilan Le; Bergametti, Françoise; Verdura, Edgard; Ludwig, Thomas; Lebenberg, Jessica; Jabeur, Waliyde; Morel, Hélène; Coste, Thibault; Demarquay, Geneviève; Bachoumas, Panagiotis; Cogez, Julien; Mathey, Guillaume; Bernard, Emilien; Chabriat, Hugues; Génin, Emmanuelle; Tournier‐Lasserve, Elisabeth

doi:10.1002/ana.26242

Cited by 13 publications

(14 citation statements)

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“…The consequences of these troubles in daily life remained moderate, leading to a diagnosis of mild cognitive impairment without dementia, even after a 6-year follow-up in 1 patient. This cognitive profile is similar to the ones detected in 3 other probands harboring similar LAMB1 variations and reported in reference 1 . Significant cognitive complaints were also present in the 2 family F1 younger patients, despite normal tests or some slightly abnormal executive scores, suggesting a possible early onset of cognitive disorders, before the age of 50.…”

Section: Discussionsupporting

confidence: 90%

“…All patients shared extensive T2 hypersignals in the brain WM, very similar to the ones described in the original publication. 1 This leukoencephalopathy was already detectable in the youngest patients in their 30s and 40s.…”

Section: Discussionmentioning

confidence: 95%

“…These “low-noise” symptoms could suggest an ischemic origin, but neurologic examinations as well as brain MRI at the time of symptoms failed to find any specific deficit or vascular lesion. 1 …”

Section: Discussionmentioning

confidence: 99%

“…This type of PTC variant escapes nonsense-mediated RNA decay (NMD) and leads to the production of an end-truncated LAMB1 protein. 1 …”

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confidence: 99%

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Extension of the Clinicoradiologic Spectrum of Newly Described End-Truncating LAMB1 Variations

et al. 2023

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ObjectivesTo refine the clinical spectrum of a very recently identified phenotype associated withLAMB1end-truncating pathogenic variations.MethodsDetailed clinical, neuropsychological, and MRI investigation of 6 patients from 2 unrelated families segregating end-truncatingLAMB1variations.ResultsAll patients harboreda LAMB1end-truncating pathogenic variation. The specific association of a hippocampal type episodic memory dysfunction and a diffuse leukoencephalopathy was observed in all 4 patients aged older than 50 years, slightly worsening over time in 2 patients with several years of follow-up. Additional unspecific neurologic symptoms are reported, such as episodes of numbness, language troubles, or faintness in these 4 patients and the 2 younger ones.DiscussionThe association of an extensive leukoencephalopathy with an episodic memory dysfunction of the hippocampal type is strongly suggestive of aLAMB1end-truncating variation in adults older than 50 years. Early cognitive complaints and imaging abnormalities might exist decades before. Additional transient manifestations can be observed, and this association should lead toLAMB1screening to avoid unnecessary invasive investigations.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

“…This type of PTC variant escapes nonsense-mediated RNA decay (NMD) and leads to the production of an end-truncated LAMB1 protein. 1 …”

mentioning

confidence: 99%

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Extension of the Clinicoradiologic Spectrum of Newly Described End-Truncating LAMB1 Variations

et al. 2023

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“… 5 12–14 In addition, the c-terminus region of LAMB1 was investigated ( online supplemental figure 1 ). 15 We evaluated the pathogenicity of the identified mutations using the ClinVar website ( https://www.ncbi.nlm.nih.gov/clinvar/ ) or previous reports. All pathogenic mutations identified using WES were confirmed using conventional Sanger’s methods.…”

Section: Methodsmentioning

confidence: 99%

High frequency ofHTRA1ANDABCC6mutations in Japanese patients with adult-onset cerebral small vessel disease

Uemura

Hatano

Nozaki

et al. 2022

J Neurol Neurosurg Psychiatry

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BackgroundThis study aimed to clarify the frequency and clinical features of monogenic cerebral small vessel disease (mgCSVD) among patients with adult-onset severe CSVD in Japan.MethodsThis study included patients with adult-onset severe CSVD with an age of onset ≤55 years (group 1) or >55 years and with a positive family history (group 2). After conducting conventional genetic tests forNOTCH3andHTRA1, whole-exome sequencing was performed on undiagnosed patients. Patients were divided into two groups according to the results of the genetic tests: monogenic and undetermined. The clinical and imaging features were compared between the two groups.ResultsGroup 1 and group 2 included 75 and 31 patients, respectively. In total, 30 patients hadNOTCH3mutations, 11 patients hadHTRA1mutations, 6 patients hadABCC6mutations, 1 patient had aTREX1mutation, 1 patient had aCOL4A1mutation and 1 patient had aCOL4A2mutation. The total frequency of mutations inNOTCH3,HTRA1andABCC6was 94.0% in patients with mgCSVD. In group 1, the frequency of a family history of first relatives, hypertension and multiple lacunar infarctions (LIs) differed significantly between the two groups (monogenic vs undetermined; family history of first relatives, 61.0% vs 25.0%, p=0.0015; hypertension, 34.1% vs 63.9%, p=0.0092; multiple LIs, 87.8% vs 63.9%, p=0.0134).ConclusionsMore than 90% of mgCSVDs were diagnosed by screening forNOTCH3,HTRA1andABCC6. The target sequences for these three genes may efficiently diagnose mgCSVD in Japanese patients.

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An AluYa5 Insertion in the 3′UTR of COL4A1 and Cerebral Small Vessel Disease

Aloui,

Neumann,

Bergametti

et al. 2024

JAMA Netw Open

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ImportanceCerebral small vessel diseases (CSVDs) account for one-fifth of stroke cases. Numerous familial cases remain unresolved after routine screening of known CSVD genes.ObjectiveTo identify novel genes and mechanisms associated with familial CSVD.Design, Setting, and ParticipantsThis 2-stage study involved linkage analysis and a case-control study; linkage analysis and whole exome and genome sequencing were used to identify candidate gene variants in 2 large families with CSVD (9 patients with CSVD). Then, a case-control analysis was conducted on 246 unrelated probands, including probands from these 2 families and 244 additional probands. All probands (clinical onset &lt;age 55 years and ≥1 first-degree relative with CSVD) were referred to the French cerebrovascular referral center between 2013 and 2023. The large-scale gnomAD structural variant database and 467 healthy individuals of French ancestry were used as a control group.Main Outcomes and MeasuresA pathogenic AluYa5 insertion was identified within the COL4A1 3′UTR in the 2 large families with CSVD. Reverse transcriptase–quantitative polymerase chain reaction (RT-qPCR), Western blot, and long-read RNA sequencing were used to investigate outcomes associated with the insertion using patient fibroblasts. Clinical and magnetic resonance imaging features of probands with variants and available relatives were assessed.ResultsAmong 246 probands (141 females [57.3%]; median [IQR] age at referral, 56 [49-64] years), 7 patients of French ancestry carried the insertion. This insertion was absent in 467 healthy French individuals in a control group (odds ratio, ∞; 95% CI, 2.78 to ∞; P = 5 × 10−4) and 10 847 individuals from the gnomAD structural variant database (odds ratio, ∞; 95% CI, 64.77 to ∞; P = 2.42 × 10−12). In these 7 patients’ families, 19 family members with CSVD carried the insertion. RT-qPCR and Western blot showed an upregulation of COL4A1 mRNA (10.6-fold increase; 95% CI, 1.4-fold to 17.1-fold increase) and protein levels (2.8-fold increase; 95% CI, 2.1-fold to 3.5-fold increase) in patient vs control group fibroblasts. Long-read RNA sequencing data showed that the insertion was associated with perturbation in the use of canonical COL4A1 polyadenylation signals (approximately 87% of isoforms transcribed from the wild type allele vs 5% of isoforms transcribed from the allele with the insertion used the 2 distal canonical polyadenylation signals). The main clinical feature of individuals with CSVD was the recurrence of pontine ischemic lesions starting at an early age (17 of 19 patients [89.5%]).Conclusions and relevanceThis study found a novel mechanism associated with COL4A1 upregulation and a highly penetrant adult-onset CSVD. These findings suggest that quantitative alterations of the cerebrovascular matrisome are associated with CSVD pathogenesis, with diagnostic and therapeutic implications.

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End‐Truncated LAMB1 Causes a Hippocampal Memory Defect and a Leukoencephalopathy

Cited by 13 publications

References 50 publications

Extension of the Clinicoradiologic Spectrum of Newly Described End-Truncating LAMB1 Variations

Extension of the Clinicoradiologic Spectrum of Newly Described End-Truncating LAMB1 Variations

High frequency ofHTRA1ANDABCC6mutations in Japanese patients with adult-onset cerebral small vessel disease

An AluYa5 Insertion in the 3′UTR of COL4A1 and Cerebral Small Vessel Disease

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