BAAT – Intrahepatic Cholestasis

BAAT, which encodes bile acid-CoA: amino acid N‑acyltransferase, has been implicated in the pathogenesis of intrahepatic cholestasis. A compelling case report described an infant with jaundice and a deficiency in amidated bile acids resulting from a transcription‑terminating mutation in BAAT (PMID:22783059). This report highlights the potential of immunostaining for BAAT as a diagnostic adjunct in suspected bile‑acid amidation defects. The clinical presentation, marked by cholestasis and jaundice, underscores the role of BAAT in normal bile acid metabolism. These findings offer a direct link between BAAT dysfunction and cholestatic liver disease. The evidence from this single, well‐characterized case supports further investigation into BAAT’s clinical relevance.

Multi‐patient studies have also associated BAAT with intrahepatic cholestasis among a panel of genes. In these studies, BAAT was identified alongside other key genes disrupted in cholestatic conditions, suggesting a broader genetic contribution to the disease phenotype (PMID:15768832). Although the exact number of affected probands was not delineated, these cohorts affirm the involvement of BAAT in a multi‑genetic setting. The combined genetic observations, albeit from a diverse set of cholestatic disorders, imply that BAAT alterations are a recurring factor in disease pathogenesis. This reinforces the clinical suspicion when BAAT variants are encountered in diagnostic sequencing panels. Overall, these studies contribute to the evolving understanding of BAAT’s impact on intrahepatic cholestasis.

While detailed segregation analyses were not extensively reported, familial clustering in cholestatic patients has been infrequently noted, suggesting a recessive mode of inheritance. The available data do not document a large number of affected relatives beyond sporadic cases, which is common in rare metabolic disorders. This absence of extensive segregation data does not preclude a significant role for BAAT, though it tempers the overall genetic score. Nonetheless, the single‐family and multi‐patient observations, when integrated with functional studies, favor a contributory role for BAAT in disease. Continued family-based analyses may eventually provide further support for its inheritance pattern. As such, current data support an autosomal recessive mode, with limited segregation evidence available to date.

The genetic evidence is further bolstered by the identification of a reported variant, c.226A>G (p.Met76Val), in affected individuals. This variant, noted in the context of a functional assessment study, conforms to established HGVS nomenclature and is detected in patients presenting features of cholestasis (PMID:12704386). Its presence provides a molecular rationale for disease causation and adds specificity to the genotype–phenotype correlation. Moreover, this mutation has been associated with a loss of BAAT enzymatic activity, supporting its pathogenic role. Although the mutational spectrum for BAAT remains to be fully defined, the recurrence of such variants across studies underscores their clinical significance. This molecular evidence is critical for diagnostic interpretation and genetic counseling.

Functional studies have yielded mechanistic insights into BAAT’s role in bile acid conjugation. Notably, in vitro assays demonstrated that the c.226A>G (p.Met76Val) variant leads to abrogation of BAAT enzyme activity, resulting in the accumulation of unconjugated bile acids (PMID:12704386). Experimental models further revealed that impaired BAAT function disrupts the enterohepatic circulation, which is consistent with the clinical picture of intrahepatic cholestasis. These functional assessments validate the biochemical consequence of the variant and align with the observed patient phenotype. The data highlight a mechanistic pathway where BAAT deficiency directly contributes to the cholestatic process. Such concordance between experimental and clinical findings reinforces the gene‑disease association.

In summary, the association between BAAT and intrahepatic cholestasis is supported by a case report with a confirmed loss‑of‑function mutation, additional multi‑patient genetic data, and robust functional evidence demonstrating disrupted bile acid conjugation. While segregation data remain minimal, the integration of these findings provides a coherent narrative that justifies refinement of diagnostic strategies. The key take‑home message is that BAAT dysfunction, as exemplified by the c.226A>G (p.Met76Val) variant, is a clinically actionable contributor to intrahepatic cholestasis, warranting its consideration in molecular diagnostic workflows.

References

• World journal of gastroenterology • 2012 • Diagnosis in bile acid-CoA: amino acid N‑acyltransferase deficiency PMID:22783059
• Annals of medicine • 2004 • Molecular basis of intrahepatic cholestasis PMID:15768832
• Nature genetics • 2003 • Complex inheritance of familial hypercholanemia with associated mutations in TJP2 and BAAT PMID:12704386

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