- Title
- Another case of nuclear speckleopathy due to a novel NKAP pathogenic variant
- Creator
- Goel, Himanshu; O'Donnell, Sheridan; Roscioli, Tony; Hart, Francesca
- Relation
- Clinical Dysmorphology Vol. 33, Issue 2, p. 79-82
- Publisher Link
- http://dx.doi.org/10.1097/MCD.0000000000000485
- Publisher
- Lippincott Williams & Wilkins
- Resource Type
- journal article
- Date
- 2024
- Description
- Nuclear speckleopathies (NSs) were a recently described group of developmental disorders with a wide spectrum of phenotypes (Regan-Fendt and Izumi, 2023). Nuclear speckles are active structures involved in the storage and processing of pre-mRNA (Burgute et al., 2014). NKAP is a highly conserved protein which localizes to nuclear speckles and interacts with other RNA-binding proteins such as heterogeneous nuclear ribonucleoproteins (hnRNPs), splicing factors and RNA helicases. NKAP activates the NF kappa B pathway, regulates the Notch signaling pathway, and is required for T-cell development (Worlitzer and Schwamborn, 2014), as well as having a role in splicing and RNA metabolism as a core component of splicing complexes (Wahl et al., 2009; Burgute et al., 2014; Fiordaliso et al., 2019). NKAP-related syndrome (MIM# 301039) is a recently described NS characterized by developmental delay, behavioral abnormalities, cardiac abnormalities, tall stature, scoliosis, camptodactyly and obesity (Fiordaliso et al., 2019). To date, only 5 hemizygous missense variants in this gene are known to cause this condition (of which one is a recurrent change). NKAP is present on the chromosome X with co-ordinates: chrX:119,920,672-119,943,751 (GRCh38/hg38). The gene is approximately 23kb long and encodes 415 amino acids over 9 exons (MANE transcript NM_024528.4). NKAP is divided into three regions, the N-terminal RSRS (Arg-Ser-Arg-Ser) tetrapeptide repeat region, the middle CIR1 interaction domain and C-terminal HDAC3 interaction and transcription repression domain (Pajerowski et al., 2009). The arginine/serine-rich domain (RS domain) has been shown to be necessary for localization to nuclear speckles (Burgute et al., 2014). The pathogenic variants in individuals with NKAP-related syndrome are clustered within the C-terminus of the NKAP protein. We are reporting here a male patient with a heterozygous de novo novel variant in NKAP with a clinical phenotype of Marfanoid Habitus with Intellectual Disability (MHID) and autism.
- Subject
- NKAP; neurodevelopmental disorder; intellectual disability; Marfanoid body habitus; autism spectrum disorder; abnormality of connective tissue
- Identifier
- http://hdl.handle.net/1959.13/1501542
- Identifier
- uon:55161
- Identifier
- ISSN:0962-8827
- Language
- eng
- Reviewed
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