LRP4 – Congenital Myasthenic Syndrome Type 17

LRP4 encodes a low-density lipoprotein receptor‐related protein critical for neuromuscular junction (NMJ) development and maintenance. It acts as a coreceptor for agrin to activate muscle‐specific tyrosine kinase (MuSK) and modulates canonical WNT signaling without affecting bone in CMS17. Site-specific variants in the third β-propeller domain of LRP4 selectively impair NMJ function while sparing skeletal phenotypes (PMID:38101565).

Autosomal recessive biallelic variants in LRP4 have been reported in three unrelated families. In the recent study, a neonate born to consanguineous parents presented with severe hypotonia, congenital diaphragmatic hernia (HP:0000776), pulmonary arterial hypertension (HP:0002092), and progressive hypoxemia; clinical exome sequencing revealed homozygosity for c.3698A>C (p.Glu1233Ala) in LRP4, with two affected siblings who died shortly after birth (3 probands in one family) (PMID:38101565). Previously, two sisters with childhood-onset CMS17 carried the same homozygous p.Glu1233Ala variant and an additional patient harbored compound heterozygous LRP4 mutations, all mapping to the third β-propeller domain (PMID:26052878).

Genetic evidence supports a strong autosomal recessive association between LRP4 and MONDO:0014578. A total of five probands across three families exhibit concordant NMJ failure and segregating third β-propeller variants. Segregation in two consanguineous families and recurrence of c.3698A>C (p.Glu1233Ala) underscore locus specificity and reproducibility. The autosomal recessive inheritance, combined with multiple unrelated affected individuals, meets ClinGen criteria for "Strong" genetic evidence.

Functional assays demonstrate that the p.Glu1233Ala variant disrupts LRP4’s ability to bind, phosphorylate, and activate MuSK in HEK293 and COS7 cells. Affected end plates in patient intercostal muscle biopsies are abnormally small with reduced acetylcholine receptor density, markedly decreased end-plate potentials, and quantal content (PMID:26052878). Treatment with albuterol sulfate improved neuromuscular transmission, confirming pathogenicity and offering pharmacologic rescue. These concordant cellular and therapeutic data provide moderate functional evidence.

The pathogenic mechanism is loss-of-function: variants in the third β-propeller domain hinder agrin-mediated MuSK activation, leading to defective synaptic differentiation and neurotransmission. The clinical overlap of hypotonia, respiratory failure, and life-threatening pulmonary complications aligns with the impaired NMJ signaling observed in vitro. No conflicting reports have emerged to date.

Integration of genetic and experimental findings establishes LRP4 as a definitive diagnostic gene for CMS17. The identification of recurrent site-specific mutations informs targeted sequencing in at-risk families and enables early therapeutic intervention. Key Take-home: Biallelic third β-propeller LRP4 variants cause autosomal recessive CMS17, guiding molecular diagnosis and offering potential for pharmacologic management.

References

• European Journal of Medical Genetics • 2024 • LRP4 site-specific variants in the third β-propeller domain causes congenital myasthenic syndrome type 17 PMID:38101565
• JAMA Neurology • 2015 • Impaired Synaptic Development, Maintenance, and Neuromuscular Transmission in LRP4-Related Myasthenia PMID:26052878

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