Universität zu Köln

Lessel, Ivana, Chen, Mei-Jan, Luettgen, Sabine, Arndt, Florian, Fuchs, Sigrid, Meien, Stefanie, Thiele, Holger ORCID: 0000-0002-0169-998X, Jones, Julie R., Shaw, Brandon R., Crossman, David K., Nuernberg, Peter, Korf, Bruce R., Kubisch, Christian and Lessel, Davor ORCID: 0000-0003-4496-244X (2020). Two novel cases further expand the phenotype of TOR1AIP1-associated nuclear envelopathies. Hum. Genet., 139 (4). S. 483 - 499. NEW YORK: SPRINGER. ISSN 1432-1203

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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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Lessel, Ivana UNSPECIFIED UNSPECIFIED UNSPECIFIED Chen, Mei-Jan UNSPECIFIED UNSPECIFIED UNSPECIFIED Luettgen, Sabine UNSPECIFIED UNSPECIFIED UNSPECIFIED Arndt, Florian UNSPECIFIED UNSPECIFIED UNSPECIFIED Fuchs, Sigrid UNSPECIFIED UNSPECIFIED UNSPECIFIED Meien, Stefanie UNSPECIFIED UNSPECIFIED UNSPECIFIED Thiele, Holger UNSPECIFIED orcid.org/0000-0002-0169-998X UNSPECIFIED Jones, Julie R. UNSPECIFIED UNSPECIFIED UNSPECIFIED Shaw, Brandon R. UNSPECIFIED UNSPECIFIED UNSPECIFIED Crossman, David K. UNSPECIFIED UNSPECIFIED UNSPECIFIED Nuernberg, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Korf, Bruce R. UNSPECIFIED UNSPECIFIED UNSPECIFIED Kubisch, Christian UNSPECIFIED UNSPECIFIED UNSPECIFIED Lessel, Davor UNSPECIFIED orcid.org/0000-0003-4496-244X UNSPECIFIED
URN:	urn:nbn:de:hbz:38-344864
DOI:	10.1007/s00439-019-02105-6
Journal or Publication Title:	Hum. Genet.
Volume:	139
Number:	4
Page Range:	S. 483 - 499
Date:	2020
Publisher:	SPRINGER
Place of Publication:	NEW YORK
ISSN:	1432-1203
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language LMNA-MUTATIONS CAUSE; LAMIN A/C; MUSCULAR-DYSTROPHY; DILATED CARDIOMYOPATHY; GENOMIC INSTABILITY; MISSENSE MUTATIONS; PROTEIN STABILITY; GENE; FORM; IDENTIFICATION Multiple languages Genetics & Heredity Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/34486