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Two novel cases further expand the phenotype of TOR1AIP1-associated nuclear envelopathies.

ABSTRACT: Biallelic variants in TOR1AIP1, encoding the integral nuclear membrane protein LAP1 (lamina-associated polypeptide 1) with two functional isoforms LAP1B and LAP1C, have initially been linked to muscular dystrophies with variable cardiac and neurological impairment. Furthermore, a recurrent homozygous nonsense alteration, resulting in loss of both LAP1 isoforms, was identified in seven likely related individuals affected by multisystem anomalies with progeroid-like appearance and lethality within the 1st decade of life. Here, we have identified compound heterozygosity in TOR1AIP1 affecting both LAP1 isoforms in two unrelated individuals affected by congenital bilateral hearing loss, ventricular septal defect, bilateral cataracts, mild to moderate developmental delay, microcephaly, mandibular hypoplasia, short stature, progressive muscular atrophy, joint contractures and severe chronic heart failure, with much longer survival. Cellular characterization of primary fibroblasts of one affected individual revealed absence of both LAP1B and LAP1C, constitutively low lamin A/C levels, aberrant nuclear morphology including nuclear cytoplasmic channels, and premature senescence, comparable to findings in other progeroid forms of nuclear envelopathies. We additionally observed an abnormal activation of the extracellular signal-regulated kinase 1/2 (ERK 1/2). Ectopic expression of wild-type TOR1AIP1 mitigated these cellular phenotypes, providing further evidence for the causal role of identified genetic variants. Altogether, we thus further expand the TOR1AIP1-associated phenotype by identifying individuals with biallelic loss-of-function variants who survived beyond the 1st decade of life and reveal novel molecular consequences underlying the TOR1AIP1-associated disorders.

SUBMITTER: Lessel I

PROVIDER: S-EPMC7078146 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Two novel cases further expand the phenotype of TOR1AIP1-associated nuclear envelopathies.

Lessel Ivana I Chen Mei-Jan MJ Lüttgen Sabine S Arndt Florian F Fuchs Sigrid S Meien Stefanie S Thiele Holger H Jones Julie R JR Shaw Brandon R BR Crossman David K DK Nürnberg Peter P Korf Bruce R BR Kubisch Christian C Lessel Davor D

Human genetics 20200213 4

Biallelic variants in TOR1AIP1, encoding the integral nuclear membrane protein LAP1 (lamina-associated polypeptide 1) with two functional isoforms LAP1B and LAP1C, have initially been linked to muscular dystrophies with variable cardiac and neurological impairment. Furthermore, a recurrent homozygous nonsense alteration, resulting in loss of both LAP1 isoforms, was identified in seven likely related individuals affected by multisystem anomalies with progeroid-like appearance and lethality within ...[more]

PMID: 32055997

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Project description:The temporal structure of animals' acoustic signals can inform about context, urgency, species, individual identity, or geographical origin. We present three independent ideas to further expand the applicability of rhythm analysis for isochronous, that is, metronome-like, rhythms. A description of a rhythm or beat needs to include a description of its goodness of fit, meaning how well the rhythm describes a sequence. Existing goodness-of-fit values are not comparable between methods and datasets. Furthermore, they are strongly correlated with certain parameters of the described sequence, for example, the number of elements in the sequence. We introduce a new universal goodness-of-fit value, ugof, comparable across methods and datasets, which illustrates how well a certain beat frequency in Hz describes the temporal structure of a sequence of elements. We then describe two additional approaches to adapt already existing methods to analyze the rhythm of acoustic sequences of animals. The new additions, a slightly modified way to use the already established Fourier analysis and concrete examples on how to use the visualization with recurrence plots, enable the analysis of more variable data, while giving more details than previously proposed measures. New methods are tested on 6 datasets including the very complex flight songs of male skylarks. The ugof is the first goodness-of-fit value capable of giving the information per element, instead of only per sequence. Advantages and possible interpretations of the new approaches are discussed. The new methods enable the analysis of more variable and complex communication signals. They give indications on which levels and structures to analyze and enable to track changes and differences in individuals or populations, for instance, during ontogeny or across regions. Especially, the ugof is not restricted to the analysis of acoustic signals but could for example also be applied on heartbeat measurements. Taken together, the ugof and proposed method additions greatly broaden the scope of rhythm analysis methods.

Dataset Information

Two novel cases further expand the phenotype of TOR1AIP1-associated nuclear envelopathies.

Publications

Two novel cases further expand the phenotype of TOR1AIP1-associated nuclear envelopathies.

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