More than keratitis, ichthyosis, and deafness: Multisystem effects of lethal GJB2 mutations

Abstract

Background: Infant death in KID syndrome is recognized; its association with specific genotypes and pathophysiology is inadequately understood. Objective: To discover characteristics that account for poor outcomes in lethal KID syndrome. Methods: We collected four new cases and nine previously reported, genotyped cases of lethal KID syndrome. We performed new molecular modeling of the lethal mutants GJB2 p.A88V and GJB2 p.G45E. Results: Infant death occurred in all patients with GJB2 p.G45E and p.A88V; it is unusual with other GJB2 mutations. Early death with those two "lethal" mutations is likely multifactorial: during life all had at least one serious infection; most had poor weight gain and severe respiratory difficulties; many had additional anatomic abnormalities. Structural modeling of GJB2 p.G45E identified no impact on the salt bridge previously predicted to account for abnormal central CO 2 sensing of GJB2 p.A88V. Limitations: Clinical review was retrospective. Conclusion: GJB2 p.G45E and p.A88V are the only KID syndrome mutations associated with uniform early lethality. Those electro-physiologically severe mutations in GJB2 reveal abnormalities in many organs in lethal KID syndrome. All KID syndrome patients may have subtle abnormalities beyond eyes, ears and skin. Early genotyping of KID syndrome births will inform prognostic discussion.

Alterations in innate immunity and epithelial cell differentiation are the molecular pillars of hidradenitis suppurativa

“…GJB2 is a specialized structure on plasma membranes of contacting adherent cells and consists of cell-to-cell channels that facilitate the transfer of ions and small molecules between cells. 67 TMPRSS11D is released from the submucosal serous glands onto mucous membrane and may play a biological role in the host defence system on the mucous membrane. 68 TCN1 is a unique glycoprotein produced by the salivary glands of the oral cavity, in response to ingestion of food and protects the acidsensitive vitamin B12.…”

Clinical, etiopathogenic, and therapeutic aspects ofKIDsyndrome

“…At least 10 out of the 12 identified mutations, including c.148G > A (p.Asp50Asn), have been associated with aberrant hemichannel behavior, resulting in elevated membrane currents, enhanced permeability to small-molecule tracers, and/or enhanced ATP release in response to a specific stimulus 4. The mutations p.Gly45Glu and p. Ala88Val are associated with uniform early lethality so early genotyping of KID syndrome births will inform prognostic discussion 16. The mutation c.148G > A (p.Asp50Asn) is also supported by the crystal structure of the connexins 26 gap junctions channel.…”

Keratitis-Ichthyosis-Deafness Syndrome: Early Death Caused by the GJB2 Mutation p.Gly12Arg

“…Improvements in skin condition, especially erythema, have been reported with oral retinoids (acitretin, isotretinoin, alitretinoin, or etretinate). Prophylactic antibiotics do not appear to prevent death (6,12). This outcome appears to be unavoidable despite intensive medical interventions, often in modern intensive neonatal care units in tertiary academic centres.…”

“…All but 1 of the 21 patients with early death reported in the literature died from infectious complications (septicaemia or pneumonia). The remaining patient died from congenital abnormality of the brainstem (6). The causes of these cutaneous infections are not well known and there are no underlying immunological anomalies.…”

“…Lilly et al (6) also reported that abnormalities in organs other than skin, cornea and inner ear may contribute to infant death in KID syndrome. For example, epithelial involvement of the oesophagus can be severe.…”