Mutations in the embryonal subunit of the acetylcholine receptor (CHRNG) cause lethal and Escobar variants of multiple pterygium syndrome

Abstract

Multiple pterygium syndromes (MPSs) comprise a group of multiple-congenital-anomaly disorders characterized by webbing (pterygia) of the neck, elbows, and/or knees and joint contractures (arthrogryposis). In addition, a variety of developmental defects (e.g., vertebral anomalies) may occur. MPSs are phenotypically and genetically heterogeneous but are traditionally divided into prenatally lethal and nonlethal (Escobar) types. To elucidate the pathogenesis of MPS, we undertook a genomewide linkage scan of a large consanguineous family and mapped a locus to 2q36-37. We then identified germline-inactivating mutations in the embryonal acetylcholine receptor gamma subunit (CHRNG) in families with both lethal and nonlethal MPSs. These findings extend the role of acetylcholine receptor dysfunction in human disease and provide new insights into the pathogenesis and management of fetal akinesia syndromes.

Figure 1.

Pedigrees for families included in this study

Figure 2.

Clinical features of subjects with CHRNG mutations and Escobar (A–H) and lethal (I and J) variants of MPS. An affected child from family MPS001 demonstrates an expressionless face and webbing of neck, axillae, and elbows (A); webbing of neck (posterior view) (B); thumb pterygium and camptodactyly (C); and popliteal pterygia and rocker-bottom feet (D). In family MPS015, an affected individual has neck pterygium (E) and pterygia and fixed flexion deformities at elbow (F), lower limbs (G), and hand (H). Elbow pterygium (I [arrow]) and muscle histopathology demonstrate an abnormal myotubular appearance (J) in a case of LMPS (from family MPS008).

Figure 3.

Identification of a common region of autozygosity in two families with MPS. The smallest region of overlap extended from D2S1363 to D2S206.

Figure 4.

Localization of MPS mutations on the CHRNG gene product that comprises a large extracellular N-terminal ligand-binding region, three hydrophobic transmembrane domains, a large intracellular region, and a fourth hydrophobic domain. All mutations mapped to the extracellular or first transmembrane domains.