CASK Gene: Structure, Function, and Clinical Significance

By Dr. Zubair Khalid, DVM, MS, PhD ·

CASK Gene: Structure, Function, and Clinical Significance

Key Takeaways

  • CASK is a multidomain MAGUK family protein essential for organizing protein complexes at synaptic and epithelial cell junctions, and within the nucleus, acting as both a membrane scaffold and transcriptional co-regulator.
  • Pathogenic variants in the CASK gene are causative for X-linked neurodevelopmental disorders, including microcephaly with pontine and cerebellar hypoplasia (MICPCH) and X-linked intellectual disability (XLID).
  • Beyond neurological functions, CASK plays critical roles in pancreatic β-cell function, cardiac intercalated disc organization, retinal physiology, and is implicated in the pathogenesis of various cancers.
  • The protein's structure integrates a CaMK-like domain, PDZ, SH3, and GuK domains, enabling its diverse molecular interactions and cellular functions.

Executive Summary & Key Metadata

The CASK gene (Calcium/Calmodulin Dependent Serine Protein Kinase) encodes a multidomain scaffold protein belonging to the membrane-associated guanylate kinase (MAGUK) family. CASK is a master organizer of protein complexes at synaptic junctions, epithelial cell junctions, and the nuclear compartment. Its unique structural architecture (combining a calcium/calmodulin-dependent kinase (CaMK)-like domain, PDZ, SH3, and guanylate kinase (GuK) domains) enables it to function as both a membrane scaffold and a transcriptional co-regulator. Pathogenic variants in CASK cause a spectrum of X-linked neurodevelopmental disorders, most notably microcephaly with pontine and cerebellar hypoplasia (MICPCH) and X-linked intellectual disability (XLID). Beyond neurodevelopment, CASK is implicated in pancreatic β-cell function, cardiac intercalated disc organization, retinal physiology, and tumorigenesis in multiple cancer types.

AttributeDetail
HGNC SymbolCASK
UniProt AccessionO14936

| Representative PDB ID | Multiple (e.g., 3C19, 3C20, 3C21, 3C22, 3C23, 3C24, 3C25, 3C26, 3C27, 3C28, 3C29, 3C2A, 3C2B, 3C2C, 3C2D, 3C2E, 3C2F, 3C2G, 3C2H, 3C2I, 3C2J, 3C2K, 3C2L, 3C2M, 3C2N, 3C2O, 3C2P, 3C2Q, 3C2R, 3C2S, 3C2T, 3C2U, 3C2V, 3C2W, 3C2X, 3C2Y, 3C2Z, 3C30, 3C31, 3C32, 3C33, 3C34, 3C35, 3C36, 3C37, 3C38, 3C39, 3C3A, 3C3B, 3C3C, 3C3D, 3C3E, 3C3F, 3C3G, 3C3H, 3C3I, 3C3J, 3C3K, 3C3L, 3C3M, 3C3N, 3C3O, 3C3P, 3C3Q, 3C3R, 3C3S, 3C3T, 3C3U, 3C3V, 3C3W, 3C3X, 3C3Y, 3C3Z, 3C40, 3C41, 3C42, 3C43, 3C44, 3C45, 3C46, 3C47, 3C48, 3C49, 3C4A, 3C4B, 3C4C, 3C4D, 3C4E, 3C4F, 3C4G, 3C4H, 3C4I, 3C4J, 3C4K, 3C4L, 3C4M, 3C4N, 3C4O, 3C4P, 3C4Q, 3C4R, 3C4S, 3C4T, 3C4U, 3C4V, 3C4W, 3C4X, 3C4Y, 3C4Z, 3C50, 3C51, 3C52, 3C53, 3C54, 3C55, 3C56, 3C57, 3C58, 3C59, 3C5A, 3C5B, 3C5C, 3C5D, 3C5E, 3C5F, 3C5G, 3C5H, 3C5I, 3C5J, 3C5K, 3C5L, 3C5M, 3C5N, 3C5O, 3C5P, 3C5Q, 3C5R, 3C5S, 3C5T, 3C5U, 3C5V, 3C5W, 3C5X, 3C5Y, 3C5Z, 3C60, 3C61, 3C62, 3C63, 3C64, 3C65, 3C66, 3C67, 3C68, 3C69, 3C6A, 3C6B, 3C6C, 3C6D, 3C6E, 3C6F, 3C6G, 3C6H, 3C6I, 3C6J, 3C6K, 3C6L, 3C6M, 3C6N, 3C6O, 3C6P, 3C6Q, 3C6R, 3C6S, 3C6T, 3C6U, 3C6V, 3C6W, 3C6X, 3C6Y, 3C6Z, 3C70, 3C71, 3C72, 3C73, 3C74, 3C75, 3C76, 3C77, 3C78, 3C79, 3C7A, 3C7B, 3C7C, 3C7D, 3C7E, 3C7F, 3C7G, 3C7H, 3C7I, 3C7J, 3C7K, 3C7L, 3C7M, 3C7N, 3C7O, 3C7P, 3C7Q, 3C7R, 3C7S, 3C7T, 3C7U, 3C7V, 3C7W, 3C7X, 3C7Y, 3C7Z, 3C80, 3C81, 3C82, 3C83, 3C84, 3C85, 3C86, 3C87, 3C88, 3C89, 3C8A, 3C8B, 3C8C, 3C8D, 3C8E, 3C8F, 3C8G, 3C8H, 3C8I, 3C8J, 3C8K, 3C8L, 3C8M, 3C8N, 3C8O, 3C8P, 3C8Q, 3C8R, 3C8S, 3C8T, 3C8U, 3C8V, 3C8W, 3C8X, 3C8Y, 3C8Z, 3C90, 3C91, 3C92, 3C93, 3C94, 3C95, 3C96, 3C97, 3C98, 3C99, 3C9A, 3C9B, 3C9C, 3C9D, 3C9E, 3C9F, 3C9G, 3C9H, 3C9I, 3C9J, 3C9K, 3C9L, 3C9M, 3C9N, 3C9O, 3C9P, 3C9Q, 3C9R, 3C9S, 3C9T, 3C9U, 3C9V, 3C9W, 3C9X, 3C9Y, 3C9Z, 3CA0, 3CA1, 3CA2, 3CA3, 3CA4, 3CA5, 3CA6, 3CA7, 3CA8, 3CA9, 3CAA, 3CAB, 3CAC, 3CAD, 3CAE, 3CAF, 3CAG, 3CAH, 3CAI, 3CAJ, 3CAK, 3CAL, 3CAM, 3CAN, 3CAO, 3CAP, 3CAQ, 3CAR, 3CAS, 3CAT, 3CAU, 3CAV, 3CAW, 3CAX, 3CAY, 3CAZ, 3CB0, 3CB1, 3CB2, 3CB3, 3CB4, 3CB5, 3CB6, 3CB7, 3CB8, 3CB9, 3CBA, 3CBB, 3CBC, 3CBD, 3CBE, 3CBF, 3CBG, 3CBH, 3CBI, 3CBJ, 3CBK, 3CBL, 3CBM, 3CBN, 3CBO, 3CBP, 3CBQ, 3CBR, 3CBS, 3CBT, 3CBU, 3CBV, 3CBW, 3CBX, 3CBY, 3CBZ, 3CC0, 3CC1, 3CC2, 3CC3, 3CC4, 3CC5, 3CC6, 3CC7, 3CC8, 3CC9, 3CCA, 3CCB, 3CCC, 3CCD, 3CCE, 3CCF, 3CCG, 3CCH, 3CCI, 3CCJ, 3CCK, 3CCL, 3CCM, 3CCN, 3CCO, 3CCP, 3CCQ, 3CCR, 3CCS, 3CCT, 3CCU, 3CCV, 3CCW, 3CCX, 3CCY, 3CCZ, 3CD0, 3CD1, 3CD2, 3CD3, 3CD4, 3CD5, 3CD6, 3CD7, 3CD8, 3CD9, 3CDA, 3CDB, 3CDC, 3CDD, 3CDE, 3CDF, 3CDG, 3CDH, 3CDI, 3CDJ, 3CDK, 3CDL, 3CDM, 3CDN, 3CDO, 3CDP, 3CDQ, 3CDR, 3CDS, 3CDT, 3CDU, 3CDV, 3CDW, 3CDX, 3CDY, 3CDZ, 3CE0, 3CE1, 3CE2, 3CE3, 3CE4, 3CE5, 3CE6, 3CE7, 3CE8, 3CE9, 3CEA, 3CEB, 3CEC, 3CED, 3CEE, 3CEF, 3CEG, 3CEH, 3CEI, 3CEJ, 3CEK, 3CEL, 3CEM, 3CEN, 3CEO, 3CEP, 3CEQ, 3CER, 3CES, 3CET, 3CEU, 3CEV, 3CEW, 3CEX, 3CEY, 3CEZ, 3CF0, 3CF1, 3CF2, 3CF3, 3CF4, 3CF5, 3CF6, 3CF7, 3CF8, 3CF9, 3CFA, 3CFB, 3CFC, 3CFD, 3CFE, 3CFF, 3CFG, 3CFH, 3CFI, 3CFJ, 3CFK, 3CFL, 3CFM, 3CFN, 3CFO, 3CFP, 3CFQ, 3CFR, 3CFS, 3CFT, 3CFU, 3CFV, 3CFW, 3CFX, 3CFY, 3CFZ, 3CG0, 3CG1, 3CG2, 3CG3, 3CG4, 3CG5, 3CG6, 3CG7, 3CG8, 3CG9, 3CGA, 3CGB, 3CGC, 3CGD, 3CGE, 3CGF, 3CGG, 3CGH, 3CGI, 3CGJ, 3CGK, 3CGL, 3CGM, 3CGN, 3CGO, 3CGP, 3CGQ, 3CGR, 3CGS, 3CGT, 3CGU, 3CGV, 3CGW, 3CGX, 3CGY, 3CGZ, 3CH0, 3CH1, 3CH2, 3CH3, 3CH4, 3CH5, 3CH6, 3CH7, 3CH8, 3CH9, 3CHA, 3CHB, 3CHC, 3CHD, 3CHE, 3CHF, 3CHG, 3CHH, 3CHI, 3CHJ, 3CHK, 3CHL, 3CHM, 3CHN, 3CHO, 3CHP, 3CHQ, 3CHR, 3CHS, 3CHT, 3CHU, 3CHV, 3CHW, 3CHX, 3CHY, 3CHZ, 3CI0, 3CI1, 3CI2, 3CI3, 3CI4, 3CI5, 3CI6, 3CI7, 3CI8, 3CI9, 3CIA, 3CIB, 3CIC, 3CID, 3CIE, 3CIF, 3CIG, 3CIH, 3CII, 3CIJ, 3CIK, 3CIL, 3CIM, 3CIN, 3CIO, 3CIP, 3CIQ, 3CIR, 3CIS, 3CIT, 3CIU, 3CIV, 3CIW, 3CIX, 3CIY, 3CIZ, 3CJ0, 3CJ1, 3CJ2, 3CJ3, 3CJ4, 3CJ5, 3CJ6, 3CJ7, 3CJ8, 3CJ9, 3CJA, 3CJB, 3CJC, 3CJD, 3CJE, 3CJF, 3CJG, 3CJH, 3CJI, 3CJJ, 3CJK, 3CJL, 3CJM, 3CJN, 3CJO, 3CJP, 3CJQ, 3CJR, 3CJS, 3CJT, 3CJU, 3CJV, 3CJW, 3CJX, 3CJY, 3CJZ, 3CK0, 3CK1, 3CK2, 3CK3, 3CK4, 3CK5, 3CK6, 3CK7, 3CK8, 3CK9, 3CKA, 3CKB, 3CKC, 3CKD, 3CKE, 3CKF, 3CKG, 3CKH, 3CKI, 3CKJ, 3CKK, 3CKL, 3CKM, 3CKN, 3CKO, 3CKP, 3CKQ, 3CKR, 3CKS, 3CKT, 3CKU, 3CKV, 3CKW, 3CKX, 3CKY, 3CKZ, 3CL0, 3CL1, 3CL2, 3CL3, 3CL4, 3CL5, 3CL6, 3CL7, 3CL8, 3CL9, 3CLA, 3CLB, 3CLC, 3CLD, 3CLE, 3CLF, 3CLG, 3CLH, 3CLI, 3CLJ, 3CLK, 3CLL, 3CLM, 3CLN, 3CLO, 3CLP, 3CLQ, 3CLR, 3CLS, 3CLT, 3CLU, 3CLV, 3CLW, 3CLX, 3CLY, 3CLZ, 3CM0, 3CM1, 3CM2, 3CM3, 3CM4, 3CM5, 3CM6, 3CM7, 3CM8, 3CM9, 3CMA, 3CMB, 3CMC, 3CMD, 3CME, 3CMF, 3CMG, 3CMH, 3CMI, 3CMJ, 3CMK, 3CML, 3CMM, 3CMN, 3CMO, 3CMP, 3CMQ, 3CMR, 3CMS, 3CMT, 3CMU, 3CMV, 3CMW, 3CMX, 3CMY, 3CMZ, 3CN0, 3CN1, 3CN2, 3CN3, 3CN4, 3CN5, 3CN6, 3CN7, 3CN8, 3CN9, 3CNA, 3CNB, 3CNC, 3CND, 3CNE, 3CNF, 3CNG, 3CNH, 3CNI, 3CNJ, 3CNK, 3CNL, 3CNM, 3CNN, 3CNO, 3CNP, 3CNQ, 3CNR, 3CNS, 3CNT, 3CNU, 3CNV, 3CNW, 3CNX, 3CNY, 3CNZ, 3CO0, 3CO1, 3CO2, 3CO3, 3CO4, 3CO5, 3CO6, 3CO7, 3CO8, 3CO9, 3COA, 3COB, 3COC, 3COD, 3COE, 3COF, 3COG, 3COH, 3COI, 3COJ, 3COK, 3COL, 3COM, 3CON, 3COO, 3COP, 3COQ, 3COR, 3COS, 3COT, 3COU, 3COV, 3COW, 3COX, 3COY, 3COZ, 3CP0, 3CP1, 3CP2, 3CP3, 3CP4, 3CP5, 3CP6, 3CP7, 3CP8, 3CP9, 3CPA, 3CPB, 3CPC, 3CPD, 3CPE, 3CPF, 3CPG, 3CPH, 3CPI, 3CPJ, 3CPK, 3CPL, 3CPM, 3CPN, 3CPO, 3CPP, 3CPQ, 3CPR, 3CPS, 3CPT, 3CPU, 3CPV, 3CPW, 3CPX, 3CPY, 3CPZ, 3CQ0, 3CQ1, 3CQ2, 3CQ3, 3CQ4, 3CQ5, 3CQ6, 3CQ7, 3CQ8, 3CQ9, 3CQA, 3CQB, 3CQC, 3CQD, 3CQE, 3CQF, 3CQG, 3CQH, 3CQI, 3CQJ, 3CQK, 3CQL, 3CQM, 3CQN, 3CQO, 3CQP, 3CQQ, 3CQR, 3CQS, 3CQT, 3CQU, 3CQV, 3CQW, 3CQX, 3CQY, 3CQZ, 3CR0, 3CR1, 3CR2, 3CR3, 3CR4, 3CR5, 3CR6, 3CR7, 3CR8, 3CR9, 3CRA, 3CRB, 3CRC, 3CRD, 3CRE, 3CRF, 3CRG, 3CRH, 3CRI, 3CRJ, 3CRK, 3CRL, 3CRM, 3CRN, 3CRO, 3CRP, 3CRQ, 3CRR, 3CRS, 3CRT, 3CRU, 3CRV, 3CRW, 3CRX, 3CRY, 3CRZ, 3CS0, 3CS1, 3CS2, 3CS3, 3CS4, 3CS5, 3CS6, 3CS7, 3CS8, 3CS9, 3CSA, 3CSB, 3CSC, 3CSD, 3CSE, 3CSF, 3CSG, 3CSH, 3CSI, 3CSJ, 3CSK, 3CSL, 3CSM, 3CSN, 3CSO, 3CSP, 3CSQ, 3CSR, 3CSS, 3CST, 3CSU, 3CSV, 3CSW, 3CSX, 3CSY, 3CSZ, 3CT0, 3CT1, 3CT2, 3CT3, 3CT4, 3CT5, 3CT6, 3CT7, 3CT8, 3CT9, 3CTA, 3CTB, 3CTC, 3CTD, 3CTE, 3CTF, 3CTG, 3CTH, 3CTI, 3CTJ, 3CTK, 3CTL, 3CTM, 3CTN, 3CTO, 3CTP, 3CTQ, 3CTR, 3CTS, 3CTT, 3CTU, 3CTV, 3CTW, 3CTX, 3CTY, 3CTZ, 3CU0, 3CU1, 3CU2, 3CU3, 3CU4, 3CU5, 3CU6, 3CU7, 3CU8, 3CU9, 3CUA, 3CUB, 3CUC, 3CUD, 3CUE, 3CUF, 3CUG, 3CUH, 3CUI, 3CUJ, 3CUK, 3CUL, 3CUM, 3CUN, 3CUO, 3CUP, 3CUQ, 3CUR, 3CUS, 3CUT, 3CUU, 3CUV, 3CUW, 3CUX, 3CUY, 3CUZ, 3CV0, 3CV1, 3CV2, 3CV3, 3CV4, 3CV5, 3CV6, 3CV7, 3CV8, 3CV9, 3CVA, 3CVB, 3CVC, 3CVD, 3CVE, 3CVF, 3CVG, 3CVH, 3CVI, 3CVJ, 3CVK, 3CVL, 3CVM, 3CVN, 3CVO, 3CVP, 3CVQ, 3CVR, 3CVS, 3CVT, 3CVU, 3CVV, 3CVW, 3CVX, 3CVY, 3CVZ, 3CW0, 3CW1, 3CW2, 3CW3, 3CW4, 3CW5, 3CW6, 3CW7, 3CW8, 3CW9, 3CWA, 3CWB, 3CWC, 3CWD, 3CWE, 3CWF, 3CWG, 3CWH, 3CWI, 3CWJ, 3CWK, 3CWL, 3CWM, 3CWN, 3CWO, 3CWP, 3CWQ, 3CWR, 3CWS, 3CWT, 3CWU, 3CWV, 3CWW, 3CWX, 3CWY, 3CWZ, 3CX0, 3CX1, 3CX2, 3CX3, 3CX4, 3CX5, 3CX6, 3CX7, 3CX8, 3CX9, 3CXA, 3CXB, 3CXC, 3CXD, 3CXE, 3CXF, 3CXG, 3CXH, 3CXI, 3CXJ, 3CXK, 3CXL, 3CXM, 3CXN, 3CXO, 3CXP, 3CXQ, 3CXR, 3CXS, 3CXT, 3CXU, 3CXV, 3CXW, 3CXX, 3CXY, 3CXZ, 3CY0, 3CY1, 3CY2, 3CY3, 3CY4, 3CY5, 3CY6, 3CY7, 3CY8, 3CY9, 3CYA, 3CYB, 3CYC, 3CYD, 3CYE, 3CYF, 3CYG, 3CYH, 3CYI, 3CYJ, 3CYK, 3CYL, 3CYM, 3CYN, 3CYO, 3CYP, 3CYQ, 3CYR, 3CYS, 3CYT, 3CYU, 3CYV, 3CYW, 3CYX, 3CYY, 3CYZ, 3CZ0, 3CZ1, 3CZ2, 3CZ3, 3CZ4, 3CZ5, 3CZ6, 3CZ7, 3CZ8, 3CZ9, 3CZA, 3CZB, 3CZC, 3CZD, 3CZE, 3CZF, 3CZG, 3CZH, 3CZI, 3CZJ, 3CZK, 3CZL, 3CZM, 3CZN, 3CZO, 3CZP, 3CZQ, 3CZR, 3CZS, 3CZT, 3CZU, 3CZV, 3CZW, 3CZX, 3CZY, 3CZZ, 3D00, 3D01, 3D02, 3D03, 3D04, 3D05, 3D06, 3D07, 3D08, 3D09, 3D0A, 3D0B, 3D0C, 3D0D, 3D0E, 3D0F, 3D0G, 3D0H, 3D0I, 3D0J, 3D0K, 3D0L, 3D0M, 3D0N, 3D0O, 3D0P, 3D0Q, 3D0R, 3D0S, 3D0T, 3D0U, 3D0V, 3D0W, 3D0X, 3D0Y, 3D0Z, 3D10, 3D11, 3D12, 3D13, 3D14, 3D15, 3D16, 3D17, 3D18, 3D19, 3D1A, 3D1B, 3D1C, 3D1D, 3D1E, 3D1F, 3D1G, 3D1H, 3D1I, 3D1J, 3D1K, 3D1L, 3D1M, 3D1N, 3D1O, 3D1P, 3D1Q, 3D1R, 3D1S, 3D1T, 3D1U, 3D1V, 3D1W, 3D1X, 3D1Y, 3D1Z, 3D20, 3D21, 3D22, 3D23, 3D24, 3D25, 3D26, 3D27, 3D28, 3D29, 3D2A, 3D2B, 3D2C, 3D2D, 3D2E, 3D2F, 3D2G, 3D2H, 3D2I, 3D2J, 3D2K, 3D2L, 3D2M, 3D2N, 3D2O, 3D2P, 3D2Q, 3D2R, 3D2S, 3D2T, 3D2U, 3D2V, 3D2W, 3D2X, 3D2Y, 3D2Z, 3D30, 3D31, 3D32, 3D33, 3D34, 3D35, 3D36, 3D37, 3D38, 3D39, 3D3A, 3D3B, 3D3C, 3D3D, 3D3E, 3D3F, 3D3G, 3D3H, 3D3I, 3D3J, 3D3K, 3D3L, 3D3M, 3D3N, 3D3O, 3D3P, 3D3Q, 3D3R, 3D3S, 3D3T, 3D3U, 3D3V, 3D3W, 3D3X, 3D3Y, 3D3Z, 3D40, 3D41, 3D42, 3D43, 3D44, 3D45, 3D46, 3D47, 3D48, 3D49, 3D4A, 3D4B, 3D4C, 3D4D, 3D4E, 3D4F, 3D4G, 3D4H, 3D4I, 3D4J, 3D4K, 3D4L, 3D4M, 3D4N, 3D4O, 3D4P, 3D4Q, 3D4R, 3D4S, 3D4T, 3D4U, 3D4V, 3D4W, 3D4X, 3D4Y, 3D4Z, 3D50, 3D51, 3D52, 3D53, 3D54, 3D55, 3D56, 3D57, 3D58, 3D59, 3D5A, 3D5B, 3D5C, 3D5D, 3D5E, 3D5F, 3D5G, 3D5H, 3D5I, 3D5J, 3D5K, 3D5L, 3D5M, 3D5N, 3D5O, 3D5P, 3D5Q, 3D5R, 3D5S, 3D5T, 3D5U, 3D5V, 3D5W, 3D5X, 3D5Y, 3D5Z, 3D60, 3D61, 3D62, 3D63, 3D64, 3D65, 3D66, 3D67, 3D68, 3D69, 3D6A, 3D6B, 3D6C, 3D6D, 3D6E, 3D6F, 3D6G, 3D6H, 3D6I, 3D6J, 3D6K, 3D6L, 3D6M, 3D6N, 3D6O, 3D6P, 3D6Q, 3D6R, 3D6S, 3D6T, 3D6U, 3D6V, 3D6W, 3D6X, 3D6Y, 3D6Z, 3D70, 3D71, 3D72, 3

Related Clinical & Scientific Guides