Figure 2.

Characterization of GANAB Mutations in Four ADPKD-Affected Families

(A) Pedigree of family M641 shows c.1914_1915delAG (p.Asp640Glnfs^∗77) (exon 17) in two affected siblings. Both sisters had basilar tip aneurysms, and II-2 also had two aneurysms detected on the left middle cerebral artery. The affected status of the parents is unclear (gray shading); I-1 had renal cell carcinoma and a ruptured aneurysm, but no reported PKD.

(B) CT scan of kidneys and liver from II-2 shows multiple kidney and occasional liver cysts.

(C) Pedigree of family 290100 shows c.1914_1915delAG in the father and son.

(D and E) MRI shows a few kidney but no hepatic cysts in II-1 (D) and a few kidney and scattered liver cysts in I-1 (E).

(F) Pedigree of family P1174 shows p.Thr405Arg (p.T405R) (c.1214C>G, exon 11) in three affected individuals; III-2, for whom no cysts were detected by ultrasound at 5 years, did not have the variant.

(G and H) MRI of III-1 shows bilateral kidney cysts (G), and ultrasound (US) of II-1 shows a single large renal cyst (H).

(I) MSA of GIIα orthologs shows that Thr405 is invariant across species. In silico mutation analysis highly predicts p.Thr405Arg (p.T405R) to be pathogenic (SIFT = 0.00, Align GVGD = C65).

(J) MSA of GANAB-like proteins shows invariant conservation of this residue.

(K) Pedigree of family M656 shows c.2690+2_+7del (IVS20) in four affected members. Splicing predictions show complete loss of the donor site. The mother (I-2), who does not have the GANAB mutation, has ∼5 kidney and ∼30 liver cysts, but no detected PKD1, PKD2, PRKCSH, or SEC63 mutations.

(L) MRI of II-3 shows small hepatic andmultiple renal cysts. Red and green arrows indicate kidney and liver cysts, respectively. Where multiple cysts are present, only representative cysts are highlighted.