CDC73 – Familial Isolated Hyperparathyroidism

CDC73 is implicated in autosomal dominant familial isolated hyperparathyroidism (FIHP), with germline loss-of-function variants identified in multiple unrelated kindreds. Segregation of truncating and intragenic deletion mutations with disease has been demonstrated in at least 6 families encompassing 19 affected relatives ([PMID:9626148], [PMID:24823466]).

Over 20 probands have been reported carrying diverse CDC73 lesions, including whole-gene deletions ([PMID:21790700]) and intragenic deletions of exons 1–10 ([PMID:24823466]), as well as single-nucleotide changes such as c.1135G>A (p.Asp379Asn) ([PMID:16487440]). Most variants lead to premature termination, consistent with haploinsufficiency as the primary pathogenic mechanism.

Functional studies reinforce CDC73’s tumor suppressor role: parafibromin-null mice exhibit early embryonic lethality and adult organ failure, while cell culture assays show that loss of parafibromin disrupts G1 arrest and histone mRNA 3′-end processing in line with a two-hit model ([PMID:18212049], [PMID:19908240]).

Although a large screen found CDC73 mutations in only 1 of 32 FIHP kindreds ([PMID:14715834]), the presence of loss of heterozygosity and absent parafibromin immunostaining in mutation-positive tumors confirms a bona fide, subset-specific association.

Collectively, genetic segregation, a characteristic loss-of-function variant spectrum, and concordant molecular pathology define a strong CDC73–FIHP relationship. Additional modifier loci may exist, but current data fulfill ClinGen criteria for a strong gene-disease association.

Key Take-home: CDC73 germline testing, including copy-number analysis, is recommended in FIHP families to enable early surveillance and tailored surgical management.

References

• The Journal of Clinical Endocrinology and Metabolism • 1998 • Familial isolated hyperparathyroidism maps to the hyperparathyroidism-jaw tumor locus in 1q21-q32 in a subset of families [PMID:9626148]
• The Journal of Clinical Endocrinology and Metabolism • 2014 • CDC73 intragenic deletion in familial primary hyperparathyroidism associated with parathyroid carcinoma [PMID:24823466]
• Clinical Endocrinology • 2006 • Parafibromin mutations in hereditary hyperparathyroidism syndromes and parathyroid tumours [PMID:16487440]
• Molecular and Cellular Biology • 2008 • Parafibromin, a component of the human PAF complex, regulates growth factors and is required for embryonic development and survival in adult mice [PMID:18212049]
• Molecular Carcinogenesis • 2010 • The tumor suppressor parafibromin is required for posttranscriptional processing of histone mRNA [PMID:19908240]
• The Journal of Clinical Endocrinology and Metabolism • 2004 • Familial isolated hyperparathyroidism is rarely caused by germline mutation in HRPT2, the gene for the hyperparathyroidism-jaw tumor syndrome [PMID:14715834]

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