TMEM5 – Walker-Warburg Syndrome

Walker-Warburg syndrome (WWS) is a severe autosomal recessive congenital muscular dystrophy characterized by brain malformations, ocular anomalies, profound hypotonia, and early mortality. Aberrant glycosylation of α-dystroglycan underlies WWS, with multiple glycosyltransferases implicated. TMEM5 (HGNC:13530), also known as RXYLT1, encodes a transmembrane ribitol‐xylosyltransferase essential for post-phosphoryl modifications of α-dystroglycan. Biallelic loss-of-function variants in TMEM5 have emerged as a cause of muscular dystrophy-dystroglycanopathy, type A (Walker-Warburg syndrome; MONDO:0000171).

Genetic evidence for TMEM5 involvement in WWS derives from both a singleton case report and a multi-patient cohort. In one full-term male with macrocephaly, respiratory distress, generalized hypotonia, hyporeflexia, and retinal degeneration, whole-exome sequencing identified a homozygous c.997G>C (p.Gly333Arg) variant in TMEM5 (PMID:39253050). A retrospective series of eleven consanguineous Saudi neonates with WWS found three additional unrelated patients harboring the same homozygous c.997G>C (p.Gly333Arg) variant in TMEM5 (PMID:33199158). In total, four unrelated probands carry homozygous TMEM5 missense variants, establishing recurrent pathogenicity in diverse populations.

All reported TMEM5 variants in WWS are missense substitutions within conserved glycosyltransferase domains, with no truncating or splice defects described. The c.997G>C (p.Gly333Arg) allele affects a residue proximal to the active site and is absent from population databases. Inheritance is strictly autosomal recessive, and no segregation beyond index cases has been documented. No founder effect outside the Saudi cohort has been proven. The current variant spectrum is limited but consistent with a hypomorphic or loss-of-function mechanism.

Functional assays support a critical role for TMEM5 in α-dystroglycan glycosylation. Cellular knockout of TMEM5 markedly reduces ribitol phosphate (RboP) addition to the phosphorylated core O-glycan of α-dystroglycan, while preserving initial phosphorylation (PMID:27601598). Rescue experiments with wild-type TMEM5 restore RboP incorporation, directly linking loss of TMEM5 activity to the biochemical defect observed in dystroglycanopathies. These data demonstrate that TMEM5 deficiency disrupts laminin-binding glycan assembly, consistent with pathogenic mechanism.

Clinically, TMEM5-related WWS presents with macrocephaly (HP:0000256), generalized hypotonia (HP:0001290), hyporeflexia (HP:0001265), respiratory distress (HP:0002098), and retinal degeneration (HP:0000546). Elevated creatine kinase concentrations reflect muscle breakdown. Neuroimaging reveals hydrocephalus, cobblestone cortex, and infratentorial malformations. Ventriculoperitoneal shunting and supportive care are standard, though most patients do not survive beyond age three. Prenatal ultrasound and MRI can identify characteristic brain anomalies in affected fetuses.

Integration of multiple independent homozygous TMEM5 variants in unrelated individuals with WWS and concordant in vitro loss-of-function assays support a Moderate ClinGen gene–disease association. Genetic evidence alone is currently Limited given the small number of reported probands, but Moderate functional data bolster pathogenicity. No conflicting reports have been published. Future segregation studies, expanded variant spectra, and animal models will further clarify TMEM5’s role. Key take-home: Biallelic TMEM5 missense variants lead to autosomal recessive Walker-Warburg syndrome by abolishing ribitol phosphate transfer to α-dystroglycan, underscoring the inclusion of TMEM5 in diagnostic gene panels.

References

• Radiology case reports • 2024 • Walker-Warburg syndrome: A case report of congenital muscular dystrophy with hydrocephalus. PMID:39253050
• Brain & development • 2021 • Neuroimaging manifestations and genetic heterogeneity of Walker-Warburg syndrome in Saudi patients. PMID:33199158
• Molecular & cellular proteomics : MCP • 2016 • Direct Mapping of Additional Modifications on Phosphorylated O-glycans of α-Dystroglycan by Mass Spectrometry Analysis in Conjunction with Knocking Out of Causative Genes for Dystroglycanopathy PMID:27601598

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