MID1 – X-linked Opitz G/BBB Syndrome

X-linked Opitz G/BBB syndrome is an X-linked recessive developmental disorder characterized by midline defects including hypertelorism, hypospadias, cleft lip/palate, laryngotracheoesophageal clefts and anal atresia. The MID1 gene, encoding a RBCC/TRIM family microtubule-associated ubiquitin E3 ligase, was first implicated through chromosomal inversion and mutation analysis in a 1997 Nature Genetics report (PMID:9354791), establishing a direct genetic link to the disease.

Genetic analyses across multiple cohorts have identified MID1 mutations in over 148 probands (PMID:11030761; PMID:12833403; PMID:15558842) segregating in at least 5 X-linked families. The inheritance pattern is X-linked recessive, with male hemizygotes fully manifesting the phenotype and carrier females showing milder hypertelorism (PMID:15558842).

The MID1 variant spectrum includes at least 30 truncating (nonsense, frameshift, splice) and over 15 missense alleles distributed throughout the RING-B-box and coiled-coil domains. In-frame insertions and deletions are also reported predominantly in the C-terminal regions, underscoring loss-of-function as the predominant mechanism (PMID:11030761; PMID:12833403; PMID:15558842).

A recently described missense variant, c.608G>A (p.Arg203Gln), was identified in two affected male siblings with total anomalous pulmonary venous connection and midline dysmorphias, expanding the cardiac phenotype of Opitz GBBB syndrome (PMID:37498300).

Functional studies demonstrate that MID1 associates with microtubules and that patient-derived missense and truncating variants abolish this interaction, forming cytoplasmic aggregates instead of normal microtubular colocalization (PMID:10077590; PMID:11371618). Furthermore, MID1 mutations impair ubiquitination of the α4 regulatory subunit of PP2A, perturbing phosphatase regulation critical for midline development.

Integration of extensive genetic segregation, variant spectrum, and concordant experimental data supports a definitive gene–disease relationship. MID1 mutational analysis is clinically actionable for diagnostic confirmation, familial testing, and potential targeted interventions in X-linked Opitz G/BBB syndrome.

References

• Nature Genetics • 1997 • Opitz G/BBB syndrome, a defect of midline development, is due to mutations in a new RING finger gene on Xp22. PMID:9354791
• Human molecular genetics • 2000 • New mutations in MID1 provide support for loss of function as the cause of X-linked Opitz syndrome. PMID:11030761
• American journal of medical genetics. Part A • 2003 • X-linked Opitz syndrome: novel mutations in the MID1 gene and redefinition of the clinical spectrum. PMID:12833403
• American journal of medical genetics. Part A • 2005 • Mild phenotypes in a series of patients with Opitz GBBB syndrome with MID1 mutations. PMID:15558842
• Proceedings of the National Academy of Sciences of the United States of America • 1999 • The Opitz syndrome gene product, MID1, associates with microtubules. PMID:10077590
• Molecular genetics & genomic medicine • 2023 • Opitz GBBB syndrome with total anomalous pulmonary venous connection: A new MID1 gene variant. PMID:37498300

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