A novel third type of recurrent NF1 microdeletion mediated by nonallelic homologous recombination between LRRC37B-containing low-copy repeats in 17q11.2

Bengesser, Kathrin; Cooper, David Neil; Steinmann, Katharina; Kluwe, Lan; Chuzhanova, Nadia; Wimmer, Katharina; Tatagiba, Marcos; Tinschert, Sigrid; Mautner, Victor‐Felix; Kehrer‐Sawatzki, Hildegard

doi:10.1002/humu.21254

Cited by 40 publications

(41 citation statements)

References 57 publications

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“…The increase in copy number of the LRRC37 duplicon appears to have evolved from a tandem organization (e.g., lemur) to one that is increasingly dispersed in the hominid lineage. Although different copies have expanded in various primate lineages, the LRRC37A and LRRC37B copies have specifically expanded in humans and great apes and are preferential sites of both recurrent inversion polymorphisms (Zody et al 2008) as well as rearrangements associated with disease (Bengesser et al 2010). Our detailed expression and transcript analyses indicate both greater diversity and a broader expression profile in humans with marked increases in the cerebellum and thymus when compared to a testis-only expression profile in the mouse.…”

Section: Discussionmentioning

confidence: 75%

Evolutionary dynamism of the primate LRRC37 gene family

et al. 2012

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Core duplicons in the human genome represent ancestral duplication modules shared by the majority of intrachromosomal duplication blocks within a given chromosome. These cores are associated with the emergence of novel gene families in the hominoid lineage, but their genomic organization and gene characterization among other primates are largely unknown. Here, we investigate the genomic organization and expression of the core duplicon on chromosome 17 that led to the expansion of LRRC37 during primate evolution. A comparison of the LRRC37 gene family organization in human, orangutan, macaque, marmoset, and lemur genomes shows the presence of both orthologous and species-specific gene copies in all primate lineages. Expression profiling in mouse, macaque, and human tissues reveals that the ancestral expression of LRRC37 was restricted to the testis. In the hominid lineage, the pattern of LRRC37 became increasingly ubiquitous, with significantly higher levels of expression in the cerebellum and thymus, and showed a remarkable diversity of alternative splice forms. Transfection studies in HeLa cells indicate that the human FLAG-tagged recombinant LRRC37 protein is secreted after cleavage of a transmembrane precursor and its overexpression can induce filipodia formation.

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Section: Discussionmentioning

confidence: 75%

Evolutionary dynamism of the primate LRRC37 gene family

et al. 2012

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“…2004) and two type 3 microdeletions (Bengesser et al. 2010), but no type 2 microdeletions (Kehrer‐Sawatzki et al. 2004).…”

Section: Discussionmentioning

confidence: 99%

126 novel mutations in Italian patients with neurofibromatosis type 1

Bianchessi¹,

Morosini²,

Saletti³

et al. 2015

Molec Gen & Gen Med

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Genetic analysis of Neurofibromatosis type 1 (NF1) may facilitate the identification of patients in early phases of the disease. Here, we present an overview of our diagnostic research spanning the last 11 years, with a focus on the description of 225 NF1 mutations, 126 of which are novel, found in a series of 607 patients (513 unrelated) in Italy. Between 2003 and 2013, 443 unrelated patients were profiled by denaturing high pressure liquid chromatography (DHPLC) analysis of 60 amplicons derived from genomic NF1 DNA and subsequent sequencing of heterozygotic PCR products. In addition, a subset of patients was studied by multiplex ligation‐dependent probe amplification (MLPA) to identify any duplications, large deletions or microdeletions present at the locus. Over the last year, 70 unrelated patients were investigated by MLPA and sequencing of 22 amplicons spanning the entire NF1 cDNA. Mutations were found in 70% of the 293 patients studied by DHPLC, thereby fulfilling the NIH criterion for the clinical diagnosis of NF1 (detection rate: 70%); furthermore, 87% of the patients studied by RNA sequencing were genetically characterized. Mutations were also found in 36 of the 159 patients not fulfilling the NIH clinical criteria. We confirmed a higher incidence of intellectual disability in patients harboring microdeletion type 1 and observed a correlation between a mild phenotype and the small deletion c.2970_2972delAAT or the missense alteration in amino acid residue 1809 (p.Arg1809Cys). These data support the use of RNA‐based methods for genetic analysis and provide novel information for improving the management of symptoms in oligosymptomatic patients.

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“…For example, one member, LRRC37B, maps at or close to the breakpoints associated with the NF1 microdeletion syndrome (Bengesser et al 2010). Two other members of the LRRC37 family, LRRC37A1 and A4, define the breakpoints of the common MAPT inversion polymorphism at Figure 3.…”

Section: Discussionmentioning

confidence: 99%

Primate segmental duplication creates novel promoters for theLRRC37gene family within the 17q21.31 inversion polymorphism region

Bekpen¹,

Tastekin²,

Siswara³

et al. 2012

Genome Res.

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The LRRC37 gene family maps to a complex region of the human genome and has been subjected to multiple rounds of segmental duplication. We investigate the expression and regulation of this gene family in multiple tissues and organisms and show a testis-specific expression of this gene family in mouse but a more ubiquitous pattern of expression among primates. Evolutionary and phylogenetic analyses support a model in which new alternative promoters have been acquired during primate evolution. We identify two promoters, Cl8 and particularly Cl3, both of which are highly active in the cerebellum and fetal brain in human and have been duplicated from a promoter region of two unrelated genes, BPTF and DND1, respectively. Two of these more broadly expressed gene family members, LRRC37A1 and A4, define the boundary of a common human inversion polymorphism mapping to chromosome 17q21.31 (the MAPT locus)-a region associated with risk for frontal temporal dementia, Parkinsonism, and intellectual disability. We propose that the regulation of the LRRC37 family occurred in a stepwise manner, acquiring foreign promoters from BPTF and DND1 via segmental duplication. This unusual evolutionary trajectory altered the regulation of the LRRC37 family, leading to increased expression in the fetal brain and cerebellum.

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A novel third type of recurrent NF1 microdeletion mediated by nonallelic homologous recombination between LRRC37B-containing low-copy repeats in 17q11.2

Cited by 40 publications

References 57 publications

Evolutionary dynamism of the primate LRRC37 gene family

Evolutionary dynamism of the primate LRRC37 gene family

126 novel mutations in Italian patients with neurofibromatosis type 1

Primate segmental duplication creates novel promoters for theLRRC37gene family within the 17q21.31 inversion polymorphism region

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