MSL3 – Basilicata-Akhtar syndrome

Basilicata-Akhtar syndrome is an X-linked neurodevelopmental disorder characterized by global developmental delay, feeding difficulties, and hypotonia. Affected individuals often present in infancy with muscle hypotonia (HP:0001252), feeding difficulties (HP:0011968), and subsequent global developmental delay (HP:0001263). Additional features include cerebellar vermis hypoplasia (HP:0001320), hearing impairment (HP:0000365), and macrocephaly (HP:0000256). The syndrome results from heterozygous or hemizygous pathogenic variants in MSL3 that cause a loss of histone H4 lysine 16 acetylation (PMID:30224647). Clinical presentation in both males and females underscores an X-linked inheritance pattern with haploinsufficiency as the likely mechanism.

Initial identification of MSL3 pathogenic variants was reported in 2018, describing truncating and missense de novo mutations in individuals with developmental delay and impaired H4K16ac (PMID:30224647). A subsequent cohort study of 25 affected individuals (15 males, 10 females) across ten centers delineated the full genotypic and phenotypic spectrum (PMID:33173220). To date, over 40 unrelated cases have been documented, including the first Indian proband identified with a hemizygous single base deletion in exon 8 (PMID:39286690). Across these cohorts, variants are predominantly de novo, with no evidence of multi-generation segregation.

The variant spectrum in MSL3 includes 10 nonsense, 6 frameshift, 4 splice site, 3 missense, 1 in-frame deletion, and 1 multi-exon deletion, clustering in exons 8–13 (PMID:33173220). Truncating alleles in the first five exons are rare, likely due to compensation by an alternative transcript. A recurrent truncating change, c.1105C>T (p.Gln369Ter), has been observed in multiple simplex cases. Missense and splice variants affect conserved residues within the chromo-barrel domain required for nucleosome interaction.

Mechanistic studies show that MSL3 is essential for the assembly and targeting of the male-specific lethal complex that mediates H4K16 acetylation (PMID:30224647). Patient-derived cells carrying MSL3 variants exhibit a pronounced global loss of H4K16ac and aberrant complex formation. Structural and in vitro binding assays reveal that the MSL3 chromo-barrel domain engages methylated H4 tails, directing complex spreading from chromatin entry sites (PMID:19029895). Disruption of this domain abrogates chromatin targeting and downstream transcriptional regulation.

Rescue experiments using histone deacetylase inhibitors partially restore H4K16ac levels and correct transcriptomic alterations in patient cells (PMID:30224647). Concordant findings in Drosophila MSL complex assembly assays, where disruption of MSL2-MSL1 interactions impairs dosage compensation, further support a conserved chromatin-based mechanism (PMID:9736618). These data confirm haploinsufficiency of MSL3 as the pathogenic basis of the syndrome and underscore the utility of epigenetic modulation as a potential therapeutic strategy.

In summary, genetic and functional evidence definitively establish MSL3 haploinsufficiency as the cause of Basilicata-Akhtar syndrome. The consistent de novo variant pattern, unbiased variant spectrum, and mechanistic coherence satisfy ClinGen criteria for a definitive gene-disease relationship. Clinical genetic testing for MSL3 variants should be incorporated into diagnostic panels for infants presenting with developmental delay, hypotonia, and feeding difficulties. Future research may explore targeted epigenetic therapies to ameliorate disease manifestations. Key Take-home: MSL3 pathogenic variants disrupt H4K16 acetylation, leading to a recognizable X-linked neurodevelopmental syndrome with clear diagnostic and therapeutic implications.

References

• Cureus • 2024 • Basilicata-Akhtar Syndrome: Unraveling an Ultrarare Cause of Developmental Delay. PMID:39286690
• Genetics in medicine • 2021 • Defining the genotypic and phenotypic spectrum of X-linked MSL3-related disorder. PMID:33173220
• Nature genetics • 2018 • De novo mutations in MSL3 cause an X-linked syndrome marked by impaired histone H4 lysine 16 acetylation. PMID:30224647
• The EMBO journal • 1998 • Complex formation by the Drosophila MSL proteins: role of the MSL2 RING finger in protein complex assembly. PMID:9736618
• Nature structural & molecular biology • 2008 • The MSL3 chromodomain directs a key targeting step for dosage compensation of the Drosophila melanogaster X chromosome. PMID:19029895

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